Cryogenic electron microscope (= Cryo-EM ), NMR, X-ray crystallography are useless for drug discovery.

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X-ray crystallography, NMR are unable to obtain many proteins' structures. Cryo-EM's resolution is too bad to know atomic mechanism.

(Fig.1)  Today's X-ray crystallography, NMR, cryo-electron microcopy are useless, unable to obtain real atomic mechanism or proteins' structures.  ← No drug discovery

The current conventional methods such as X-ray crystallography, NMR, cryogenic-electron microscopes (= Cryo-EM ) are useless for drug development, unable to clarify atomic mechanisms of proteins, enzymes.

X-ray crystallography is useless, unable to obtain structures of proteins that can not be crystallized.

In the most popular X-ray crystallography, the target proteins must be purified, concentrated and crystallized, and the diffraction or interference patterns of X-ray passing through the crystallized protein are measured to estimate proteins' structures.

↑ The drawback of this X-ray crystallography is that most proteins can Not be crystallized ( this-2nd-paragraph,  this-lower-limitation ), and the static protein structures obtained by this X-ray crystallography (= recorded in protein databank or PDB ) are often different from dynamical proteins inside bodies.

So this X-ray crystallography (and AI, Alphafold trained on static proteins of this PDB ) is useless for drug development, unable to clarify atomic mechanism of dynamical biological reactions or diseases.

This 1. crystalline samples says
"The requirement for a crystalline sample is one of the most significant restrictions of x-ray crystallography...
Complex, big, or membrane-embedded proteins frequently cause them to fail"

NMR is also useless, able to know only some small proteins.

NMR (= nuclear magnetic resonance spectroscopy irrelevant to quantum mechanics ) measures the nuclear magnetic moment or spin to determine 3-dimensional structures of some small proteins.

NMR can deal with only very small molecules (= clarifying the very important membrane's proteins' structures is impossible ), and often fails to capture the atomic structure when the nuclear magnetic moments are small or samples are aggregated ( this-p.2,  this-last-conclusion,  this-middle-disadvantage of NMR ).

The 5~6th paragraphs of this site say
"large and dynamic biomolecular complexes, membrane proteins, and macromolecular assemblies that have traditionally been challenging for other structural biology techniques like X-Ray crystallography or nuclear magnetic resonance (NMR) spectroscopy."

Cryogenic electron microscopy (= Cryo-EM ) can Not know atomic structures of proteins.

Cryogenic-electron microscopes (= Cryo-EM ) bombard the rapidly-frozen protein samples with high-energy electrons to estimate the target proteins' structures.

The problem is this cryo-EM (= single particle analysis or SPA ) based on detecting randomly-scattered electrons often have bad resolutions (= 3 ~ 4Å,  this-p.11-conclusion ) that can Not distinguish single atoms (= single atomic size is 1Å ).

↑ So cryo-EM unable to know atomic mechanism of proteins is useless for drug development.

Cryo-EM needs to prepare purified homogenous protein samples to estimate the protein structure by averaging many scattered electrons, which is extremely difficult, ( this-key steps in protein sample preparation ), unable to investigate membrane's proteins ( this-3~4th-paragraphs ).

Cryo-EM's resolution is bad, unable to measure atoms.

This-7th-paragraph (2025) says "However, cryo-EM's resolution typically doesn't match the atomic-level precision of crystallography,"

This-introduction-1st-paragraph (2025) says
"However, building atomic models from cryo-EM density maps remains challenging in many cases."

This-middle-current limitations and challenges in cryo-EM (2025) says
"Membrane proteins can be difficult to purify"
"The high-energy electron beam can damage the sample, limiting the resolution of the reconstruction."

Cryo-ET resolution is much worse, useless.

Cryo-ET (= cryogenic-electron tomography ) has much worse resolution (= 20~50Å, this-The foundation of Cryo-ET ) that cannot distinguish each single atom, either.

Only practical multi-probe atomic force microscopes can clarify atomic mechanism of proteins and cure diseases.

The only way to know the precise atomic mechanism and structures of proteins is to use multi-probe atomic force microscopes directly manipulating single atoms and molecules, which is hampered by the current unphysical quantum mechanical atomic model.

↑ The practical multi-probe atomic force microscopes can directly see and distinguish single atoms of proteins.

If we observe and gradually break the target proteins by artificial chemical breaking, we can know any 3-dimensional and inner atomic structures of proteins by multi-probe atomic force microscopes.

So replacing today's useless single-probe-tip atomic force microscopes by practical multiple probes is necessary and urgent to clarify any proteins' atomic mechanisms and structures.

And the multi-probe atomic force microscopes can develop new effective drugs by directly confirming the biological interactions between the target proteins and the newly-designed drug molecules.  → cure diseases

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