Dataset Information

Dissecting the Influence of Protein Flexibility on the Location and Thermodynamic Profile of Explicit Water Molecules in Protein-Ligand Binding.

ABSTRACT: Explicit water molecules in the binding site of proteins play a crucial role for protein-ligand association. Recent advances in computer-aided drug discovery methodology allow for an accurate prediction of the localized position and thermodynamic profile of water molecules (i.e., hydration sites) in the binding site. The underlying calculations are based on MD simulations of explicit water molecules in a restrained protein structure. However, the ligand-binding process is typically associated with protein conformational change that influences the position and thermodynamic properties of the hydration site. In this manuscript, we present the developments of two methods to incorporate the influence of protein conformational change on hydration sites either by following the conformational transition step-by-step (method I) or to match the hydration sites of the two transition end states using local coordinate systems (method II). Using these methods, we highlight the difference in the estimated protein desolvation free energy with and without inclusion of protein flexibility. To the best of our knowledge, this is the first study that explicitly studies the influence of protein conformational change on the position and thermodynamic profiles of water molecules and provides methodology to incorporate protein flexibility into the estimation of the desolvation free energy.

SUBMITTER: Yang Y

PROVIDER: S-EPMC5397387 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Dissecting the Influence of Protein Flexibility on the Location and Thermodynamic Profile of Explicit Water Molecules in Protein-Ligand Binding.

Yang Ying Y Lill Markus A MA

Journal of chemical theory and computation 20160818 9

Explicit water molecules in the binding site of proteins play a crucial role for protein-ligand association. Recent advances in computer-aided drug discovery methodology allow for an accurate prediction of the localized position and thermodynamic profile of water molecules (i.e., hydration sites) in the binding site. The underlying calculations are based on MD simulations of explicit water molecules in a restrained protein structure. However, the ligand-binding process is typically associated wi ...[more]

PMID: 27494046

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Project description:Protein-protein interactions (PPIs) have been identified as a vital regulator of cellular pathways and networks. However, the determinants that control binding affinity and specificity at protein surfaces are incompletely characterized and thus unable to be exploited for the purpose of developing PPI inhibitors to control cellular pathways in disease states. One of the key factors in intermolecular interactions that remains poorly understood is the role of water molecules and in particular the importance of solvent entropy. This factor is expected to be particularly important at protein surfaces, and the release of water molecules from hydrophobic regions is one of the most important drivers of PPIs. In this work, we have studied the protein surface of a mutant of the protein RadA to quantify the thermodynamics of surface water molecules. RadA and its human homologue RAD51 function as recombinases in the process of homologous recombination. RadA binds to itself to form oligomeric structures and thus contains a well-characterized protein-protein binding surface. Similarly, RAD51 binds either to itself to form oligomers or to the protein BRCA2 to form filaments. X-ray crystallography has determined that the same interface functions in both interactions. Work in our group has generated a partially humanized mutant of RadA, termed MAYM, which has been crystallized in the apo form. We studied this apo form of MAYM using a combination of molecular dynamics (MD) simulations and inhomogeneous fluid solvation theory (IFST). The method locates a number of the hydration sites observed in the crystal structure and locates hydrophobic sites where hydrophobic species are known to bind experimentally. The simulations also highlight the importance of the restraints placed on the protein in determining the results. Finally, the results identify a correlation between the predicted entropy of water molecules at a given site and the solvent-accessible surface area and suggest that correlations between water molecules only need to be considered for water molecules separated by less than 3.2 Å. The combination of MD and IFST has been used previously to study PPIs and represents one of the few existing methods to quantify solvent thermodynamics. This is a vital aspect of molecular recognition and one which we believe must be developed.

Dataset Information

Dissecting the Influence of Protein Flexibility on the Location and Thermodynamic Profile of Explicit Water Molecules in Protein-Ligand Binding.

Publications

Dissecting the Influence of Protein Flexibility on the Location and Thermodynamic Profile of Explicit Water Molecules in Protein-Ligand Binding.

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