Oct 26, 2018

Are protein-ligand complexes robust structures?

BioRxiv : the Preprint Server for Biology
Maciej MajewskiXavier Barril

Abstract

The predominant view in structure-based drug design is that small-molecule ligands, once bound to their target structures, display a well-defined binding mode. While this is convenient from a design perspective, it ignores the fact that structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, any potential benefit of a rigid binding mode will have to be balanced against the entropic penalty that it entails. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Here we investigate two diverse sets of structures, comprising 79 drug-like and 27 fragment ligands, respectively. We focus on hydrogen bond interactions (469 in total), as they have been described as essential for structural stability. We find that 75% of complexes are anchored by at least one robust hydrogen bond, the remaining 25% either form loose complexes or are constrained by other interactions types. The first type of complexes generally combine a single anchoring point with looser regions, thus balancing order and disorder. Completely constricted protein-ligand complexes are rare and seem to fulfil a functional necessity. Structural stability analy...Continue Reading

  • References
  • Citations

References

  • We're still populating references for this paper, please check back later.
  • References
  • Citations

Citations

  • This paper may not have been cited yet.

Mentioned in this Paper

Muscle Rigidity
Complex (molecular entity)
DNA Stability Analysis
Equilibrium
Pharmacologic Substance
Structure
Ligands Activity
Enzyme Stability
Ligands
Anchoring Activity

About this Paper

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

Related Papers

International Journal of Molecular Sciences
Sheng-You Huang, Xiaoqin Zou
Acta Crystallographica. Section D, Biological Crystallography
Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme
M Isiguro
© 2020 Meta ULC. All rights reserved