An investigation of structural stability in protein-ligand complexes reveals the balance between order and disorder
Open Access
- 17 September 2019
- journal article
- research article
- Published by Springer Nature in Communications Chemistry
- Vol. 2 (1) , 1-8
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. However, structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, it entails an entropic penalty that counters complex formation. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Since hydrogen bonds have been described as essential for structural stability, here we investigate 469 such interactions across two diverse structure sets, comprising of 79 drug-like and 27 fragment ligands, respectively. Completely constricted protein-ligand complexes are rare and may fulfill a functional role. Most complexes balance order and disorder by combining a single anchoring point with looser regions. 25% do not contain any robust hydrogen bond and may form loose structures. Structural stability analysis reveals a hidden layer of complexity in protein-ligand complexes that should be considered in ligand design.Keywords
Funding Information
- EC | Horizon 2020 Framework Programme (675899)
- Ministerio de Economía y Competitividad (SAF2015-68749-R)
- Generalitat de Catalunya (2014 SGR 1189)
- Barcelona Supercomputing Center
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