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Structure and Function of Water In Biomolecular Systems

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Water molecules are a key component of biomolecular systems, clustering at well-defined hydration sites and acting as ordered structural elements at binding interfaces. Thus, the mediation of intermolecular interactions by water molecules has important consequences for processes such as molecular recognition and protein folding. We will describe the study of water networks in two contexts:

  1. Protein Folding – Understanding protein folding remains a key scientific and engineering challenge. Two key questions in protein folding are (a) why folded proteins prefer a collapsed state and (b) how folded proteins transform from an extended state to a collapsed state. Computational studies are well-placed to address the first question due to the ability to analyse systems at atomic-level resolution. Here we consider multiple independent simulations of the villin headpiece domain to quantify the contributions of different interactions to the energy of the native and fully extended states.[1] In particular, we focus on four of these components: protein-protein hydrogen bonding interactions, non-polar protein-protein interactions, hydrophobic desolvation, and mutual solvation of surface residues. The results will be of interest to both experimentalists and theoreticians in the field of protein structure.
  2. Protein-Ligand Binding – Analysis of complexes from the PDBbind database shows that small-molecule ligands in complex with proteins are bound to an average of 4.6 water molecules. Here we describe the utility of inhomogeneous fluid solvation theory (IFST) a statistical mechanical method that decomposes hydration free energies into contributions from different hydration sites. IFST accurately assesses the opposing thermodynamic contributions of the entropic gain for displacing a highly-ordered water molecule and the enthalpic loss for breaking water-protein hydrogen bonds. IFST agrees with other computational methods in predicting that a single water molecule can contribute more than -17 kcal/mol to the free energy of a hydrated protein.[2] In the context of a protein–ligand binding, a binding affinity of -17 kcal/mol corresponds to picomolar binding. It will be shown that predicting thermodynamic properties of water molecules at binding interfaces can provide useful information for ligand design against novel targets and identify untapped potential in well-known drug targets.[3]

[1] DJ Huggins “Studying the role of cooperative hydration in stabilizing folded protein states” – Journal of Structural Biology 196 (3), 394-406 (2016) [2] DJ Huggins “Quantifying the Entropy of Binding for Water Molecules in Protein Cavities by Computing Correlations” – Biophysical Journal 108, 928-936 (2015) [3] S Vukovic, PE Brennan, DJ Huggins “Exploring the Role of Water in Molecular Recognition: Predicting Protein Ligandability Using a Combinatorial Search of Surface Hydration Sites”– Journal of Physics: Condensed Matter (2016)

This talk is part of the Biological and Statistical Physics discussion group (BSDG) series.

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