Top page (9/15/2024)
The current mainstream "science" is false
Deepmind Alphafold AI
(F.1) The current molecular simulating methods such as unrealistic quantum mechanics and time-consuming molecular dynamics (= the current fastest method, though ) are main culprits of stopping our scientific progress forever.
See this page
(Fig.2) Molecular dynamics is useless, taking too much time in unnecessary computation of its artificially-created fake energies called force fields.
Basically, all the current protein docking methods and softwares can deal only with rigid (= static ) proteins, Not suited for flexibly-changing proteins ( this introduction ), and their false prediction rates are impractically high ( this p.12 ).
↑ Protein docking prediction tools are unable to deal with actual proteins' motion or conformational change required for explaining protein-molecular interactions (= even flexible docking tools only deal with the change of small molecular ligand or only a few side chains, they can Not change protein backbones flexibly, this 14~16th paragraphs, this abstract-top ), hence, impractical for drug discovery.
Due to the extremely useless quantum mechanics (= QM ), the (pseudo-)classical molecular dynamics (= MD ) is the current only option for describing and simulating molecular and protein's dynamical conformational changes and interactions ( this p.2-last, this p.2 2nd-paragraph, this p.1-left-lower, this p.2-lower ).
Besides this mainstream molecular dynamics (= MD ), there is random-moving method called Monte Carlo (= MC, this p.5-right ). This MC method trying to move atoms or protein in a random disorderly way is time-consuming and often unable to predict or explain correct protain conformational change ( this last paragraph, this p.2 3rd paragraph, this p.3~p.4-top )
As a result, only the molecular dynamics (= MD ) remains as a tool to simulate proteins' movement or conformational change, though this most-widely-used molecular dynamics is still unable to cure deadly diseases such as cancers and Alzheimer.
Why are all the current molecular simulating methods such as quantum mechanics and (pseudo-classical) molecular dynamics (= MD ) too useless to use for describing atomic bahavior and curing deadly diseases such as cancers, Alzheimer and HIV ?
The main reason for it is that not only the old quantum mechanics but also the current fastest molecular dynamics (= MD ) has to perform the extremely-time-consuming impractical calculations of artificially-created (fake) total or potential energies called "force fields" to simulate even very simple atomic motion ( this p.3-right, this p.14-34 ), because unphysical quantum mechanics cannot give concrete shape to each atom and molecule.
In even the latest researches, this mainstream molecular dynamics (= MD ) takes as many as a few days to simulate only micro-second protein's conformational change ( this 10th-paragraph ), which extremely-time consuming MD method cannot simulate or explain important biological reactions such as protein folding which reactions normally take milliseconds~seconds~hours which are far longer than microsecond-time scale accessible by the current protein simulating method or molecular dynamics ( this 3~5th paragraphs, this p.1~p.2, this p.23-middle ).
In our daily life utilizing various things (= made of atoms ) for practical application, when we want to construct practical buildings, cars, planes or laptops, all we have to do is just simply prepare parts and components, move and combine them.
↑ That's all. There is No need to perform unrealistically time-consuming calculations of all total (potential) energies of all atoms and electrons composing parts, buildings and cars to construct them ! ← It means the current mainstream time-consuming quantum mechanics and molecular dynamics are unnecessary for building practical machines and simulating actual molecules. ← Quantum mechanics blocks scientific progress.
Humans have already had the useful technology of measuring and manipulating each single atom and molecule freely as we like, using atomic force or scanning tunnel microscopes for 30 years.
So in the same way as building practical cars, planes and laptops, we should be able to build useful nano-machines by moving and putting together atoms and molecules for medical treatment or developing drugs really effective for cancers and Alzheimer.
But this practical use of individual atoms for building useful nano-devices has been hampered by the current dead-end mainstream old pseudo-physics, quantum mechanics ( this 4th-paragraph ), its unphysical quasi-particle models, and (pseudo-classical) molecular dynamics for a long time
Due to the unrealistically-spreading electron cloud or wavefunction (= with No boundary ), the quantum mechanical atomic model can neither exert real Coulomb force for forming molecular covalent bonds ( this p.3-4, this p.4,5-Fig,1 ) nor define each molecular realistic shape for exerting contact force or Pauli repulsion only in microscopic atoms. → extremely time-consuming molecular dynamical pseudo-potential energy had to be created.
Quantum mechanics needed to artificially create unphysical concepts called " exchange energies (= expressed as exchange integral )" lacking real (exchange) force ( this p.5-upper ) to express these molecular attractive covalent bonds ( this p.11 ) or strong Pauli repulsion (= contact or normal force ) between molecules, showing No physical meaning ( this p.11, this p.6(or p.5)-upper ).
Due to this unphysical "exchange energy (= caused by pseudo-kinetic energy change due to the interference of an single pseudo-electron's wavefunction spreading over all atoms )," both the quantum mechanics and molecular dynamics based on it are unable to deal with real forces directly ( this p.9-10 ).
Instead, they have to always perform very time-consuming calculations of the meaningless total energies, artificially-created pseudo-potential energies called "force fields" in order to simulate even simple atomic motion and generate fictitious force by differentiating those unphysical total (or potential ) energies at short time intervals repeatedly many, many times which time-consuming method is a main culprit of making the current quantum mechanics and molecular dynamics unfeasible and impractical forever.
In the real practical world, we do Not need to consider these meaningless time-consuming total energies of all atoms and electrons composing parts, cars and planes to build them. We just consider each component's shape, hardness, elasticity, move and combine them using "real (push or pull) force" to build cars, planes and practical computers.
But in the impractical quantum mechanical and molecular dynamics world, we cannot directly consider or use each atomic concrete shape and (contact ) force applied on it, instead, physicists are forced to take too much time in meaninglessly calculating the artificially-created total or potential energies called force fields with many (imperfect) freely-adjustable parameters.
This (pseudo-classical) force field potentials are Not real potentials due to their lack of real electrons.
This molecular dynamics force field pseudo-potential tries to express actual bond attractive or Pauli repulsive energies using pseudo-classical spring-like potential energies.
Physicists have to artificially choose many, many ad-hoc parameters for these pseudo-bond length and angle-related energies from experimental results or researchers' experience ( this p.9 ).
The molecular dynamics unable to use real electrons have to artificially give fictional non-integer atomic (partial) charge to each atom one by one, which force field bond parameters must be deliberately changed in different molecules. ← No common legitimate principle
In most cases, these artificially-created force field pseudo-potential energies give the wrong simulating results ( this p.2-first-paragraph, this p.4-last-paragraph ).
And physicists have to repeatedly calculate "fictitious force" acting on each atom one by one by differentiating those artificially-created force field potential energies at each very small time step (= 2 femtosecond or 2fs ) to gradually and extremely slowly move each atom one by one ( this p.5-p.24, this p.2-right,p.13-Table5 ).
The current mainstream molecular simulating method of unreasonably differentiating artificially-created force-field potentials to move each atom by the fictitious force, many, many times makes even the current fastest molecular dynamics (= MD ) impractical, taking too much time = about several days only for simulating very short-time (= microsecond-scale ) protein's conformational change ( this p.4-lower,p.10-lower )
↑ This current extremely time-consuming molecular-simulating methods ( this p.5-Fig.2 ) are the main culprits of stopping our scientific progress for curing diseases forever ( this p.3-4 ).
This p.4,p.11 says
"To ensure numerical stability, the time steps in an MD (= molecular dynamics ) simulation must be short, typically
only a few femtoseconds (10–15 s) each. Most of the events of biochemical interest—for
example, functionally important structural changes in proteins—take place on timescales of
nanoseconds, microseconds, or longer. A typical simulation thus involves millions or
billions of time steps. This fact, combined with the millions of interatomic interactions
typically evaluated during a single time step, causes simulations to be very computationally
demanding.."
"..Finally, important biomolecular processes, including ligand binding and conformational change, often take place on timescales longer than those accessible by classical all-atom MD (= molecular dynamics ) simulation. For systems with about 50,000 atoms (typical for a moderately sized, solvated protein), one GPU can currently simulate a microsecond in a few days."
↑ The current unrealistically-time-consuming and inefficient molecular-simulating methods are definitely incapable of simulating the actual multiple proteins and enzymes involved in long disease-forming and healing processes ( which takes days ~ years ) for developing really effective drugs.
Even in the recent researches, the current "fastest" impractical molecular dynamics (= MD ) can handle only a single molecular or protein's change for extremely short time = only microseconds ( this p.2-results, this p.2-left, p.9-last, this p.12 ), which are far shorter than the actual biological reactions that take minites, hours, days..
This or this p.2-left-lower~right says
".. the possibility of
simulating the association process of a ligand to a target with
conventional molecular dynamics (cMD) for processes in the
range of a few microseconds. Despite the progress of
computing power, cMD remains very expensive in computational time and simulating dissociation events in the range of minutes to hours is still challenging."
So all the current biologists and medical researchers are unable to utilize these impractical quantum mechanics and molecular dynamics, and all they can rely on is the old conventional macroscopic biological tools such as PCR without looking into important atomic or electron interactions ( this p.1-method, this p.20-22, this p.14 ).
↑ Enzymes such as restriction enzymes, DNA polymerase, and reverse transcriptase used in PCR necessary for the biological research were purified from the natural bacteria and viruses ( this p.1-second-paragraph ), instead of being designed by humans or (useless) quantum mechanics. ← Unrealistic quantum mechanical or molecular dynamical atomic model contributed nothing to biological research.
Hence, the current deadend biology and medical technology, which do Not consider actual atomic interactions in cells at all, can never progress or cure deadly cancers and Alzheimer diseases whose treatments need the precise understanding of microscopic atomic interactions in proteins and receptor reactions.
We must immediately discard these old useless quantum mechanical model and molecular dynamics contradictong the real practical world in order to restart progressing the current stalled science and treat deadly cancers.
(Fig.3) Molecular dynamics cannot directly utilize real force, instead, it has to perform very time-consuming calculations of differentiating artificially-created total energies or force fields, many, many times ! ← It takes "many years" to simulate only one short-time biological reaction. ← impractical forever
Even the current fastest molecular simulating method called molecular dynamics (= MD ) takes an unrealistically enormous amount of time to simulate only one molecule or protein.
For example. simulating only one-microsecond motion of one molecule or one protein takes a day or more time ( this 2nd-paragraph, this p.10-right-3rd-paragraph, this p.5, this p.2-lower,p.4-upper ).
It means the simulation of actual biological reaction on the time scale of only one second would take more than 1000 years, which is completely impractical ( this p.1-right-2nd-paragraph ).
This 5th-paragraph says
"On advanced super computers, computation speeds are measured in microsecond biological time (10-6s) per day of calculation. A calculation of a single millisecond trajectory requires 103 days, or about three years. (← a calculation of a second trajectory requires 3000 years !)"
This p.2-left says
" in eukaryotes, bacteria,
and archaea.. folding times range from
microseconds to tens of minutes. Even with anticipated continuing increases in computing power, simulating the folding of
these larger slower folding proteins using standard molecular
dynamics (MD) simulations will remain out of reach for the
foreseeable future"
↑ This current unrealistically time-consuming, inefficient molecular-simulating method is the reason why our atomic nano-technology stops progressing, hence, many diseases such as cancers and Alzheimer are incurable forever.
The solution to this current deadend science and innovation is very simple.
In the practical daily life, we can easily describe, simulate and manipulate the motions of multiple objects such as balls and gears, each of which consists of many atoms and electrons, for arbitrary periods of seconds, hours, or days,.. which manipulation and estimation can be done speedily, taking almost No time.
In the same way, we should be able to easily simulate the motion of a (real tangible) molecule or protein pushed by some (real) forces for 1 millisecond, second or minute, even without taking many days or years that are required for the impractical molecular dynamics or more time-consuming quantum mechanical calculations ( this p.23-middle ).
The point is all the current molecular simulating methods including molecular dynamics are unable to directly use (real) forces or give real shape to each atom due to the quantum mechanical unphysical Pauli exchange energy.
↑ To move or simulate such an unrealistically shapeless atom or molecule (= each quantum wavefunction must always spread to infinity with No boundary or shape ) inside protein without using real force (= we cannot predict how the shapeless atoms collide with each other and move after the collision ), quantum mechanics and molecular dynamics have to rely on unrealistically-time-consuming methods of trying to getting (fictitious) force from artificially-created total energy called force field at short time intervals, repeatedly many, many times. ← No practical use.
First, molecular dynamics has to guess and create the fictitious total or potential energies (= U or V ) of all atoms called force fields with many adjustable parameters ( this p.4-5 ), which must determine the final conformational change, without using much simpler realistic atomic model with concrete shape like macroscopic objects.
Then, by differentiating this artificially-created pseudo-potential or force fields (= U or V ) to obtain the fictitious force F (= ∇U or ∇V ) applied on each atom one by one ( this p.14-34, this p.29, this p.1-4 ).
And based on this calculated fictitious force F, physicists need to update each atomic position (= r ) and velocity (= v ) one by one, taking an enormous amount of time ( this p.22-28, this p.29, this p.17-31, this p.12-19 ).
Unlike our practical daily life directly using (real) forces on tangible objects with concrete shapes, in this impractical inconvenient molecular dynamics methods of calculating fictitious forces applied on each atom (= with No tangible concrete shape due to unrealistically inseparable electrons ) one by one through pseudo-potential energy U (or V ), physicists have to discretize the whole time into many, many small time steps, each step time length must be less than 2 femtosecond (= fs ) or 2 × 10-15 second ( this p.2-first-paragraph ).
Because in order to describe the case where the external force applied on one atom of the whole protein or object is immediately transmitted (= ~fs infinitesimal time steps ) to all atoms of the protein (= this transmitted force should immediately determines in which direction or how the whole protein or object is moved in real molecules ), the (impractical) molecular dynamics simulation needs the very time-consuming iterative calculations and updating of each atomic potential energy, force and position at extremely short time intervals (= 2 fs, this time and size limitation ).
↑ If we directly consider real applied forces and treat the protein as a real object with concrete shape (= like the components for cars and buildings ), we can easily predict or simulate in which direction or how the protein or object is moved when some external object's force is applied on it.
But in the inconvenient molecular dynamics, which cannot directly utilize real applied force (= contact or normal force by quantum Pauli repulsion that is Not admitted as real force ) or the immediately-transmitted force (= molecular bond exchange energy with No real force ), physicists have to take an unrealistically large amount of time in repeatedly differentiating pseudo-potential energy U to obtain the fictitious force applied on each atom and update each atomic position one by one at extremely short-time intervals (= 2 fs, this p.2-right ).
So the only several-microsecond (= μs ) motion of a molecule or protein can be simulated by the current molecular-simulating researches ( this p.11-12 molecular dynamics simulation ), which is far from the time scales (= seconds, minutes, or hours ) required for describing actual biological systems and protein's behavior ( this p.10-lower ).
↑ Simulating only one-second motion of one molecule or protein pushed by external force would take as many as 1000 years even in the current fastest molecular dynamics (= MD ), which cannot be applied to the practical medicine or drug development ( this 4th-paragraph, this p.49 ).
If we forget these current meaninglessly-time-consuming molecular simulating methods such as quantum mechanics and molecular dynamics, we should be able to easily treat and move each molecule or protein for arbitrarily long time length like moving a real component for constructing practial buildings, cars, and machines.
Only in the practical macroscopic world, we are allowed to treat each object (= consisting of atoms ) and force (= contact force caused by Pauli repulsion ) as real tangible objects with definite shapes and hardness.
When it comes to the microscopic unphysical quantum mechanical world, suddenly we are Not allowed to treat each molecule or atomic force as real tangible things (= due to unrealistically inseparable electrons ). ← This is clearly inconsistent double-standard employed by the current physicists due to contradictory quantum mechanical preposterous rule.
(Fig.4) Directly use real force = speedy and practical.
Differentiating artificial total energies to obtain fictitious forces repeatedly, many, many times takes an unrealistically much time. ← Impractical molecular dynamics
The reason why quantum mechanics and molecular dynamics (= MD ) are extremely time-consuming and useless for practical application is these models cannot utilize real forces directly.
Instead, the molecular dynamics (= MD ), which is the current fastest molecular-simulating method, has to artificially create ( fake ) total or potential energies called force fields (= U or V ), and differentiate the total energy to get all fictitious forces F (= ∇U or ∇V ) applied on all individual atoms one by one, repeatedly, many, many times, which takes an unrealistically large amount of time ( this p.5-14,p.24 ).
For example, we think about the practical case of pulling and bending some steel stick (= quantum mechanical unphysical infinitely-spreading wavefunction cannot give concrete shape to this stick, contrary to reality ) to use it as components for constructing some useful buildings and cars.
↑ Of course, we do Not need to perform very time-consuming calculations of meaningless total (or potential) energies of all atoms and electrons constituting these steel stick, buildings or cars in the practical process of using components and parts.
But in the current impractical molecular-simulating methods such as quantum mechanics and molecular dynamics (= MD ), even this simple process of pulling and bending a steel stick cannot be described, hence, if we applied these current impractical mainstream molecular-simulating methods also to our macroscopic daily life, we could Not utilize practical buildings, cars, planes or laptops now !
As I said, due to the paradoxical quantum mechanics falsely considering even real contact force to be unreal force caused by unphysical Pauli exchange energy lacking real (exchange) force instead of real contact forces between real objects with concrete shapes, all the current molecular-simulating method such as molecular dynamics has to artificially create fake total ( potential ) energies called force fields by adjusting many free bond parameters, instead of directly using real forces.
Force field pseudo-potentials of the molecular dynamics include intermolecular Lennard-Jones potential that represents Pauli repulsive exchange enregies lacking real forces. ← This MD fictitious force field potential always bridging two atoms can Not treat each atom as a separate particle with boundary or shape.
Then, physicists have to go through very time-consuming processes of differentiating (= ∇ ) these artificially-created total or force-field potential energies U or V to obtain fictitious transient forces F applied on each different atom one by one ( this p.2-right, this p.19-32 ) instead of simply estimating contact forces working between objects (= stick and other things ) with concrete shapes.
And based on this pseudo-forces by differentiating the artificial total energies, they have to update each atomic position and velocity at each small-time step (= each time step length is only 2 femtoseconds or fs ), repeatedly, many, many time, until the the whole stick is bent to the final shape.
↑ The molecular dynamics calculation of even this very simple stick's motion or bending takes an enormous amount of time ( this p.2-3 ).
Even simulating only the one-microsecond motion of a molecule or a object takes more than one day ( this 5th-paragraph, this p.11-2nd-paragraph ) !
So if we take one minute to bend this steel stick, even the current fastest molecular dynamics takes more than 10000 years to simulate it ! ← completely impractical ( this p.10-lower ).
In the same way, also when we want to move and rotate some amino acids for building some practical molecular machines, all we need to do is push the molecule or amino acids with concrete shape by (real) force.
↑ In this practical use of atoms and components, it is completely unnecessary to calculate meaningless total (or potential ) energies, which take an unrealistically enormous amount of time.
In the current molecular dynamics, we cannot utilize real forces directly (= because we cannot estimate real contact forces between unrealistically-shapeless quantum mechanical atoms ). Instead, physicists are always forced to perform extremely time-consuming calculations of differentiating the artificially-created pseudo-potential energies or force-fields to obtain pseudo-forces applied on each atom, one by one ( this p.4,15 ), and update each atomic position, velocity, repeatedly, many, many times, until the target amino-acide is moved or rotated to the final configuration.
Calculating these total energies or artificially-created force-field potential energies is completely meaningless.
Because due to quantum mechanical inability to solve multi-electron Schrödinger equations, which means all the quantum mechanics and molecular dynamics are unable to predict total energy values of unknown atoms and molecules ( this p.9 ), physicists have to compare their calculated total energies and experimental values to readjust the parameters of their artificially-chosen wavefunctions or force-field pseudo-potentials, after all ( this p.17, this p.4-fifth-paragraph ).
↑ So we do Not need to perform such a meaninglessly time-consuming calculation of total energy which cannot be predicted by the current molecular-simulating methods, and instead, we should use the experimentally-obtained atomic data such as each atomic and molecular shape, size and basic surface property from the beginning.
Like knowing the shape, size and basic properties such as hardness, elasticity and stickiness of each component for building practical cars and machines, we can know the concrete shape, size and basic properties of each atom and molecule using the current atomic force microscopes.
↑ Based on these actually-observed atomic data, we can gradually build bigger molecular devices or machines by putting together atoms and molecules with already-known properties (confirmed by atomic force microscope or something ), confirming the basic properies of the newly-built slightly-bigger molecular componens one by one, and repeating these processes until building the final bigger molecular-machines, like building practical cars, planes and laptops.
The current unscientific mainstream theory such as quantum mechanics and Einstein relativity has fatal defect, they cannot give each atomic concrete shape and real force applied on it. ← This means unrealistic quantum mechanics cannot give definite shapes even to macroscopic tangible steel sticks, buildings or cars !
In order to give and designate each atomic concrete shape and contact force that is generated by Pauli principle repulsion ( this p.4-last ), we need some real substance or medium filling space causing real (= experimentally-verified ) de Broglie wave destructive interference felt as real Pauli repulsion or contact force, which contradcts Einstein relativity unreasonably rejecting the real space medium and adopting the contradictory quantum virtual particles with unreal imaginary mass to explain electromagnetic force.
The present mainstream physicis is double-standard, and inconsistent.
↑ In the actucal macroscopic daily life, we naturally and automatically give the concrete shape to each object, and treat the contact or normal force (= Pauli repulsion ) as real forces, while only in microscopic unphysical quantum mechanical world, they suddenly forbids us from designating each atomic shape or treating Pauli repulsion as real force.
Though this Pauli repulsion or contact force, which gives each atomic shape, is experimentally measurable also on the atomic scale like the macroscopic contact force ( this p.6, this p.1-left ) ! = unscientific double-standard !
So the current mainstream science that deliberately tries to treat the macroscopic (= daily-life ) and microscopic (= unphysical quantum mechanical ) worlds differently under different physical principles (= one treats Pauli repulsion as real force and gives concrete shapes to atoms, the other does Not ) is self-contradictory and false.
Even the current fastest molecular-simulating method = (pseudo-classical) molecular dynamics (= MD ) takes unrealistically much time to simulate even a very short-time (= 1 μs ) motion of a single molecule or a protein, hence, completely useless for biology, medical research and developing effective drugs.
Physicists try to introduce various ad-hoc rough approximations to shorten the calculation time of MD, but all these ad-hoc approximations failed.
One of these approximations is coarse-grained (= CG ) molecular dynamics where some number of atoms are artificially treated as one big bead-like pseudo-atom.
↑ Of course, if they try to treat an actual molecule consisting of multiple atoms with various complicated shapes as one pseudo-atom with spherical bead shape (= correctly, this coarse-grained bead-like pseudo-atom also has No definite shape except for pseudo-force-field potentials around it ), this cannot describe the original exact molecular or protein reactions ( this abstract ) = trade-off between accuracy and efficiency.
↑ In many actual protein and enzymatic reactions, distinguishing each different atom related to different bond breaking and formation is very important, which crucial information is lost in this very rough coarse-grained approximation ( this last, this p.9-limitation, this p.1-right, this p.2-left-2nd-paragraph ).
This p.23-right-5. says
" the compromise between accuracy and computational efficiency. The smaller the number of explicitly treated united atoms (or pseudoatoms of coarse-grained model ) representing fragments of protein chains, the faster simulation, and the lower accuracy.. the coarse-grained modeling of solvent and protein interaction effects with small molecules is very challenging.. "
"Current force fields are Not accurate enough, and it is possible to obtain different results using different force fields, even the all-atom ones.."
Even if this very rough coarse-grained (= CG ) approximation is used, it is also extremely time-consuming and impractical. Even in the recent researches, the simulating time by this coarse-grained approximation is only less than microseconds ( this p.10-coarse-grained, this-lower Conclusions, this p.4-right ) which cannot be applied to actual longer biological or drug reactions ( this p.7-limitations ).
Because this approximate coarse-grained molecular dynamics (= CG-MD ) also has to calculate meaningless fictitious total energies (= new ad-hoc force-fields must be prepared for different coarse-grained models, this p.6-left ) to obtain the pseudo-force acting on each pseudo-atom with very short time steps (< 20 femtoseconds or fs, this p.20, this p.10-method ) repeatedly many many times (~ 107 steps repeated, this p.12-left-CGMD ).
As shown in this p.5-Fig.2, even this rough approximate coarse-grained molecular dynamics takes one day to simulate even the very-short 1-microsecond protein motion ( this p.3-Coarse grain molecular dynamics ).
Actually, the current coarse-grained molecular dynamics cannot simulate even the one-millisecond molecular motion ( this p.11-first-paragraph ) without sacrificing accuracy. ← The current miserable situation does Not change at all.
Another approximate molecular dynamics called Gaussian accelerated molecular dynamics (= GaMD ) tries to accelerate the molecular dynamics simulation by artificially adding boost-potentials to the original force-field potential ( this p.2 ).
In some proteins, this GaMD becomes slightly faster than the conventional MD (= cMD ), but even this GaMD cannot simulate the protein's motion of longer than one millisecond ( this p.9-left, this p.15, this p.6, this p.2-results ) ← The molecular dynamics is still impractical stopping our science progress.
Unlike the molecular dynamics, Monte-Carlo (= MC ) simulation method tries to move each atom and molecule randomly ( this p.2, this p.16-lower ), forgetting real forces and energies, causing random sampling errors ( this p.2-right-lower, this last-paragraph, this p.26-lower ).
Hence, this random, disorderly Monte-Carlo methods cannot simulate the complicated protein's (especially deterministic) conformational change ( this p.2-lower, this 1.2-disadvantage, this p.1-right-1st-paragraph this p.2-first paragraph, this p.2-first-paragraph ).
This p.2-right says
"The Monte Carlo
simulation is unsuitable for such a crowded-atom system
because most trial conformations result in rejection by atomic bumps."
This Monte Carlo Simulation Results Explained section says
"there is No guarantee that the most expected outcome will occur, or that actual movements will not exceed the wildest projections."
So No current molecular simulating methods can be utilized for effective drug discovery or curing intractable diseases, and our science is dead-ended, stuck in this current fastest impractical molecular dynamics, forever.
As I said, the solution to this deadend situation is simple, we just admit the actually-measurable atomic forces such as Pauli repulsion (= contact force ) as real forces, and give it some real force carriers (= which equals giving concrete tangible shape to each atom and molecule ) to avoid the meaninglessly time-consuming calculations of total energies.
(Fig.5) Push one part (= one atom ) of a rigid stick → this applied force is transmitted immediately to all the atoms of the stick → the whole rigid stick is moved at the same time by this force. ← Even this simple motion cannot be simulated by the impractical molecular dynamics !
In our daily life or the practical world, when we push one end of a rigid stick, this applied force is immediately transmitted through all atoms composing the entire stick, and then, the entire stick is moved or rotated at the same time.
↑ Even this simple motion of a stick is impossible to simulate by the current alleged-fastest inconvenient molecular simulating method or (pseudo-classical) molecular dynamics.
In this impractical molecular dynamics (= MD ) that can neither directly deal with real applied (or transmitted ) force nor give concrete tangible shape to each atom, first, physicists have to prepare the fictitious total or potential energies of all atoms called force fields with many adjustable bond parameters.
In this unphysical mainstream molecular dynamical method depending on fictitous force field potentials always bridging two atoms, it is impossible to treate each individual atom as a separate particle with definite shape or boundary.
Then, they differentiate this artificially-created pseudo-potential (= V or U ) or force field to obtain pseudo-forces (= F = ∇V or ∇U ) acting on each atom one by one.
Based on these pseudo-forces, physicists have to update each atomic position (= coordinate ) and velocity one by one at each time step whose time interval should be less than 2 femtoseconds (= 2 fs = 2 × 10-15 seconds ), and repeat this time-consuming steps of calculating pseudo-energy and force on each atom many, many times until the target object is moved to the final position ( this p.5-12, p.24 ).
As I said, no matter what ad-hoc approximations are used, the current fastest molecular dynamics takes more than one day just to simulate the one-microsecond motion of a molecule or a protein ( this 5th-paragraph ).
So it is impossible to simulate the actual biological reactions on the scale of milliseconds ~ hours, which would take even the current fastest molecular dynamics more than 10000 years !
The main culprit that makes all the current molecular simulating methods useless and time-consuming is the unphysical quantum mechanical Pauli exchange energies lacking real (exchange) force ( this p.4, this p.5-upper ), as I said, many times.
Due to lack of real physical (exchange) forces expressing molecular covalent bonds connecting neighboring atoms and Pauli repulsion, which is contact force acting between the finger pushing and the pushed atom (or object ), the quantum mechanics and molecular dynamics are unable to describe even the real applied force transmitted through the rigid stick.
If we can utilize the concept of real force or contact force like in the daily life where constructing practical buildings and cars needs "real force", we can easily predict in which direction each object will be moved even without performing the extremely time-consuming calculations of meaningless total energies of all atoms.
For example, billiard players can predict in which direction each billiard ball will be moved when one ball hits other balls by looking at each ball's position, shape, motion and the applied force. ← No need to calculate the meaningless total energy of all atoms composing billiard balls with concrete shapes !
↑ The point is, in our daily life, we can give definite shape, size and force to each tangible object such as parts, cars, buildings, planes and laptops, so we can easily predict the motions of objects even without performing the time-consuming meaningless total energies repeatedly many, many times.
On the other hand, unrealistic quantum mechanics is incapable of giving definite shape and real force to each atom, which means quantum mechanics cannot give concrete shape or force even to tangible macroscopic objects such as a rigid stick and buildings !
According to the impractical quantum mechanics, even the simple contact or normal force (= Pauli repulsion ) exerted when we push some object is Not treated as real force.
Instead, unrealistic quantum mechanics must express even this actually-measurabale contact force by unphysical antisymmetric wavefunctions that lead to the unphysical exchange energy integrals allegedly causing the electron's pseudo-kinetic energy changes (= higher kinetic energy = Pauli repulsion, this p.9-10, this introduction-3rd-paragraph, this p.13-2nd-paragraph, lower kinetic energy = molecular bond ) inside the fake total energy with No real force ( this p.1-left-lower ).
↑ This unphysical quantum mechanical Pauli antisymmetric wavefunction requires each single electron to always exist in all different atoms in the whole material as the unrealistically spreading wavefunction, which makes each atom and electron inseparable, hence, concrete shape cannot be given to this unphysically inseparable quantum mechanical atom.
No concrete shape cannot be given to each atom and object by the impractical quantum mechanics that needs to rely on the extremely-time-consuming calculations of meaningless total energy including the unphysical exchange energy.
In this unrealistic quantum mechanics that never admits the actual contact force as real (Pauli repulsive) force, physicists unreasonably claim we can Not even touch any objects, no matter how closely we approach the object !
Quantum mechanics and molecular dynamics disagree with the experimental observations where we can actually measure the concrete shape and size of not only macroscopic tangible object but also each microscopic atom through the contact force or Pauli repulsion ( this p.6, this p.1-left ).
As a result, in order to use each atom and molecule as practical tools for building some useful nano-devices, we have to admit actually-felt Pauli repulsion or molecular covalent bond as real forces, and give some real substance to express this real Pauli repulsion or each atomic concrete shape, which is impossible in the current unrealistic quantum mechanics and paradoxical Einstein relativity rejecting the real substance or medium filling the space.
(Fig.6) Real objects, billiard balls and atoms have "concrete shapes", so these motions or the time when these objects hit each other are easily predictable without performing the meaningless time-consuming quantum mechanical or molecular dynamical energy calculations. → practical use
In this real practical world, we can easily predict when two objects or billiard balls with concrete shapes and velocities hit each other even without performing the meaningless time-consuming quantum mechanical or molecular dynamics (= MD ) calculations.
When two objects or billiard balls hit each other, the contact or normal force prevents them form penetrating each other (= to keep the objects' or atomic shapes ), and this contact (repulsive) force makes these collided objects bounce back from each other by real Pauli repulsion (= Not kinetic energy claimed by contradictory quantum mechanical Pauli exchange energy ) between two hitting objects.
All these real tangible objects and billiard balls are made of atoms and molecules, which means each atom and molecule also must have concrete shape and size to rebound each other by contact force.
Actually, we can know each atomic precise size and shape by directly measuring the contact force (= caused by Pauli repulsive force ) of each atom using the current already-existing technology of atomic force microscopes ( this p.4 fifth-paragraph ).
But unlike these real objects or billiard balls with concrete shapes and sizes, the unphysical quantum mechanical atoms or molecules are Not allowed to have their concrete shapes due to the unphysical quantum mechanical Pauli principle's exchange energy.
Quantum mechanics claims the contact (normal) force is caused by Pauli principle's (unphysical) antisymmetric wavefunctions or Slater determinants where each single electron must always exist in all different atoms including two distant atoms that are about to hit each other, unrealistically.
In this unreal quantum mechanical world, when two objects or atoms approach and hit each other, these two objects or atoms are Not allowed to have concrete shapes due to the inseparable single electron spreading over all different atoms obeying unphysical Pauli antisymmetric wavefunction.
So physicists can Not predict when these two (unreal) quantum mechanical objects or atoms lacking concrete shapes hit each other.
As a result, even in the current fastest molecular dynamics (= MD ) simulation, they are forced to perform very time-consuming meaningless calculations of unphysical total (or exchange ) energies U or V (= called "force fields" ) and fictitious forces F by differentiating the total or exchange energies at extremely short-time intervals (= each calculation time step must be extremely short = about 2 fs or 2 × 10-15 second due to inability to predict when two atoms hit each other and change their direction suddenly ) many, many times (= ~ 107 iterative calculations ) just to simulate the simple atomic motion of moving for very short time ( this p.5-12, p.24 ).
↑ If they choose each force or atomic position's updating time step longer than 10 fs or 10 × 10-15 s to save time, two rigid objects or atoms may mistakingly penetrate or overlap each other without noticing they already touch each other in this inconvenient unphysical quantum mechanics or molecular dynamics that cannot utilize real atoms with known concrete shapes due to unphysical Pauli exchange energy.
↑ These serious errors caused by choosing longer time step paradoxically increase (or decrease ) total energy (= this erroneous violation of energy conservation law is called energy explosion or blow-up ) by two atoms wrongly overlapping with each other due to Not noticing Pauli repulsive barriers around the unrealistic quantum mechanical shapeless atoms ( this p.10-first-paragraph, this results and discussion, this 5~7th-paragraphs, this p.27-28, this p.8-2.2, this 7th-paragraph ).
This p.1-last~p.2 says
"if a very small value of time step (= each time step length is 2 fs ) is used, it will not be
efficient since it takes a very long calculation time. However, unfortunately, the MD integration algorithm becomes
unstable at large time step size. If too large a time step τ (= ex. longer than 10~100 fs ) is used, the motion of particles becomes
This p.28 says
"If the timestep is much too long, the system can become unstable and
blow up (energies become very large) due to overlap of atoms (= due to the unrealistic quantum mechanical atoms with No concrete shapes, this p.28, this blowing-up section )."
This 7th paragraph says
"Increasing the time step another factor of 2 to 4 fs finally causes the system to "blow up". The timestep is so long that the atoms deeply interpenetrate each other's steeply repulsive wall between steps. The resulting force is now so large that the atoms fly off.."
↑ If each atom or molecule has definite shape like the realistic objects such as billiard balls, the unreasonable molecular dynamical errors like "overlapping atoms" would never happen, and we can easily predict and control the motions of those realistic atoms and molecules with concrete shapes like predicting billiard balls' motions without time-consuming meaningless molecular dynamics energy calculations.
Simulating the atomic motion for just less than microseconds takes unrealistically-much time = more than one day even in the current fastest molecular dynamics that must perform very-time-consuming meaningless repeated calculations of all atomic positions and fictitious energy-forces with very short (= 2fs ) time steps many, many times to avoid the unexpected atomic penetration or energy conservation errors ( this p.3-right, this 3-5th-paragraphs, this 2-3th paragraphs, this p.6-first-paragraph ).
↑ All these current impractical mainstream molecular-simulating methods such as quantum mechanics and molecular dynamics are wrong and double standard, because they are clearly inconsistent with the actual macroscopic separable objects (= made of atoms ) with concrete shapes and sizes.
In the practical macroscopic world, we treat all buildings, cars, planes, laptops, parts and billiard balls.. as real objects with concrete shapes.
This is why we can easily move and put together these real parts with concrete shapes and size to build useful cars, planes, laptops and buildings even without performing the meaningless time-consuming quantum mechanical or molecular dynamics calculations of total (or exchange ) atomic energies.
Because if we know the concrete shape and size of each object and billiard ball, we can easily know when these two objects or billiards balls hit each other without conducting the unnecessary time-consuming quantum mechanical energy calculations.
The motions of gears and electrons' flow inside practical machines and laptops can be easily controlled and predicted because each gear and electron's circuit has definite shape, and when and how each gear or electron hits other things can be easily predicted.
On the other hand, quantum mechanics tries to describe the actual contact (or normal ) force as the unphysical Pauli antisymmetric wavefunctions that obligate all different atoms to share the same inseparable single electron (= ex. electron-1 ) simultaneously where No clear boundary exists between these two unrealistically inseparable atoms with No distinct shapes (= due to the inseparable spreading electron shared ).
↑ This unphysical quantum mechanical Pauli repulsive exchange energy (= expressed as exchange integral ) caused by this Pauli antisymmetric wavefunctions is Not a real repulsive potential energy but the fictitiously-increasing kinetic energy ( this p.9-10, this p.13 2nd-paragraph, this introduction-3rd-paragraph ) that cannot give concrete shape or real repulsive force to each atom or molecule (= kinetic energy causing exchange energy is opposite to potential energy that gives shapes ).
So the lack of concrete shapes, sizes and real contact forces ( this p.4 ) in these unphysical quantum mechanical atoms and molecules makes it impossible for us to estimate when and how each object or atom hits other objects or atoms for avoiding penetrating each other unrealistically, hence, easy prediction and simulation of unphysical quantum mechanical atoms or proteins lacking concrete shapes are impossible.
The particles' motions caused by the realistic Coulomb electric force among the realistic electric charges (such as actually movable electrons and nuclei ) should be able to be easily estimated and simulated even without performing the meaninglessly-time-consuming iterative total (or exchange) energy calculation of molecular dynamics (= electric charges and electrons' flow can be easily and precisely controlled by applying electric field as shown in the current practical computers and laptops ).
But quantum mechanics and molecular dynamics are unable to explain the actual molecular covalent bonds by the realistic Coulomb electric force, insteand, they have to rely on the unphysical exchange energy allegedly caused by the fictitious kinetic energy decrease (= Not by Coulomb potential energy or real force ) which intangible exchange interaction or integral ( this p.11 ) cannot be simulated realistically or rapidly unlike the rapid and efficient classical Coulomb force's model.
The current fastest molecular simulating method or molecular dynamics (= MD ) tries to describe intermolecular Coulomb force attraction (= not intramolecular covalent bonds ) or van der Waals intermolecular force by giving fictitious different non-integer atomic partial charges, which are just freely-adjustable parameters, to different atoms ( this Figure.1 ).
For example, in order to express the weak intermolecular attractive hydrogen bonds (= caused by Coulomb electric force ), the hydrogen atoms are often given various fictitious non-integer positive partial charges and the oxygen atoms are given various fictitious negative partial charges that are freely-adjustable non-existent pseudo-charges ( this p.1-introduction, this p.7 ).
But when these hydrogen and oxygen atoms that have already bound to other atoms and formed covalent bonds get closer to each other than this attractive hydrogen bond length, Pauli repulsive force must start to kick in and prevent them from approaching further ( this p.7-Pauli ).
In the current problematic mainstream physics based on unrealistic quantum mechanics and Einstein relativity, the space is supposed to contain No real substance or medium except for electron or proton's electric charges causing only Coulomb electric force, hence, the current mainstream physics cannot express the source of this actual Pauli repulsive force using real substance or things.
In the current atomic theory based on quantum mechanical Schrodinger equation whose hydrogen atomic energies agree with Bohr's realistic atom, there are only two concepts of Coulomb electric potential energy and de Broglie wave that can be used for explaining the atomic energies ( this p.14-last ).
So if we want to express this actually-measurable Pauli repulsive force that is clearly different from Coulomb electric force by using some real substance, only de Broglie wave (destructive) interference is left in '(wrongly) empty space' except for Coulomb electric charge.
This electron's de Broglie wave (destructive) interference has been actually observed in many experiments such as Davisson-Germer and two-slit interference.
In order to explain these actually-observed two-slit interference and diffraction of an electron, some real substance or medium filling space is definitely necessary, if you do Not want to rely on unrealistic quantum mechanical many worlds or dead-alive-cat superposition.
Anyway, the current mainstream science is clearly inconsistent and self-contradictory, because they try to treat only the macroscopic objects such as cars, planes and billiard balls as tangible objects with definite shapes exerting real contact force, and treat the microscopic molecule and atom as the unphysical ghost-like objects lacking concrete shapes and (exchange) force.
Though the macroscopic tangible objects are made of the microscopic atoms and molecules, the unreasonable quantum mechanics tries to treat these macroscopic objects and microscopic atoms as completely different inconsistent things, which is clearly the unreasonable double standard, hence, unscientific and wrong.
To know the precise shape and size of each atom for estimating real Pauli repulsion, we need to improve the current atomic force microscope and use at least two probes for getting rid of influence of other atoms.
2023/2/14 updated. Feel free to link to this site.
