Preference of Small Molecules for Local Minimum Conformations when Binding to Proteins
Author Information
Author(s): Wang Qi, Pang Yuan-Ping
Primary Institution: Mayo Clinic, Rochester, Minnesota, United States of America
Hypothesis
Why do many ligands reportedly not adopt local minimum conformations when binding to proteins?
Conclusion
Ligands generally prefer to adopt local minimum conformations when binding to proteins, but excessive energy minimization can lead to misleading results.
Supporting Evidence
- All 100 ligand conformations in their protein-bound ligand crystal structures are nearly identical to their local minimum conformations.
- Excessive energy minimization can lead to misleading conclusions about ligand conformations.
- 69 of the 100 ligands have local minimum conformations with mwRMSDs of ≤0.50 Å when using the NEM procedure.
Takeaway
This study shows that small molecules like ligands usually like to fit into their best shapes when they attach to proteins, but if we try too hard to make them fit perfectly, it can backfire.
Methodology
The study used normal-mode analysis (NMA) to analyze 100 crystal structures of protein-bound ligands and assessed their conformations through energy minimization.
Limitations
Further studies with other force fields are desirable to confirm the findings.
Digital Object Identifier (DOI)
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