Abstract
A molecular dynamics replica exchange based method has been developed that allows rapid identification of putative ligand binding sites on the surface of biomolecules. The approach employs a set of ambiguity restraints in replica simulations between receptor and ligand that allow close contacts in the reference replica but promotes transient dissociation in higher replicas. This avoids long-lived trapping of the ligand or partner proteins at nonspecific, sticky, sites on the receptor molecule and results in accelerated exploration of the possible binding regions. In contrast to common docking methods that require knowledge of the binding site, exclude solvent and often keep parts of receptor and ligand rigid the approach allows for full flexibility of binding partners. Application to peptide-protein, protein-protein and a drug-receptor system indicate rapid sampling of near-native binding regions even in case of starting far away from the native binding site outperforming continuous MD simulations. An application on a DNA minor groove binding ligand in complex with DNA demonstrates that it can also be used in explicit solvent simulations.
Highlights
Protein-ligand complex formation triggers the majority of biological processes in cells and mediates the effect of drug molecules
Simulations employing an implicit Generalized Born (GB) solvation model were performed with the OBC (Onufriev, Bashford, and Case) GB model [27] and a 12 Å Born radius cutoff combined with a cutoff for electrostatic calculations of 20 Å
During Molecular Dynamics (MD) simulations of biomolecular encounter processes such “sticky” sites can result in many locally trapped binding states that are separated by barriers with long associated life times
Summary
Protein-ligand complex formation triggers the majority of biological processes in cells and mediates the effect of drug molecules. Effective widely applied molecular docking methods are based on a systematic docking search largely neglecting conformational flexibility or including flexibility of binding partners only approximately [1,2,3,4,5]. During a systematic search stage empirical scoring functions are employed that allow rapid scoring of generated complexes based on surface complementarity and pairwise interaction potentials [4,5]. In a second step docking solutions are refined using methods that allow for conformational changes of the partner molecules (e.g. molecular dynamics simulations) and possible rescoring of selected
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