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SUMMARY:Structure and Function of Water In Biomolecular Systems - David Hu
 ggins (University of Cambridge)
DTSTART:20170309T120000Z
DTEND:20170309T130000Z
UID:TALK71345@talks.cam.ac.uk
CONTACT:William Grant
DESCRIPTION:Water molecules are a key component of biomolecular systems\,\
 nclustering at well-defined hydration sites and acting as ordered\nstructu
 ral elements at binding interfaces. Thus\, the mediation of\nintermolecula
 r interactions by water molecules has important\nconsequences for processe
 s such as molecular recognition and protein\nfolding. We will describe the
  study of water networks in two contexts:\n\n# Protein Folding - Understan
 ding protein folding remains a key\nscientific and engineering challenge. 
 Two key questions in protein\nfolding are (a) why folded proteins prefer a
  collapsed state and (b)\nhow folded proteins transform from an extended s
 tate to a collapsed\nstate. Computational studies are well-placed to addre
 ss the first\nquestion due to the ability to analyse systems at atomic-lev
 el\nresolution. Here we consider multiple independent simulations of the\n
 villin headpiece domain to quantify the contributions of different\nintera
 ctions to the energy of the native and fully extended states.[1]\nIn parti
 cular\, we focus on four of these components: protein-protein\nhydrogen bo
 nding interactions\, non-polar protein-protein interactions\,\nhydrophobic
  desolvation\, and mutual solvation of surface residues. The\nresults will
  be of interest to both experimentalists and theoreticians\nin the field o
 f protein structure.\n# Protein-Ligand Binding - Analysis of complexes fro
 m the PDBbind\ndatabase shows that small-molecule ligands in complex with 
 proteins\nare bound to an average of 4.6 water molecules. Here we describe
  the\nutility of inhomogeneous fluid solvation theory (IFST) a statistical
 \nmechanical method that decomposes hydration free energies into\ncontribu
 tions from different hydration sites. IFST accurately assesses\nthe opposi
 ng thermodynamic contributions of the entropic gain for\ndisplacing a high
 ly-ordered water molecule and the enthalpic loss for\nbreaking water-prote
 in hydrogen bonds. IFST agrees with other\ncomputational methods in predic
 ting that a single water molecule can\ncontribute more than -17 kcal/mol t
 o the free energy of a hydrated\nprotein.[2] In the context of a protein
 –ligand binding\, a binding\naffinity of -17 kcal/mol corresponds to pic
 omolar binding. It will be\nshown that predicting thermodynamic properties
  of water molecules at\nbinding interfaces can provide useful information 
 for ligand design\nagainst novel targets and identify untapped potential i
 n well-known\ndrug targets.[3]\n\n[1] DJ Huggins “Studying the role of c
 ooperative hydration in\nstabilizing folded protein states” - Journal of
  Structural Biology 196\n(3)\, 394-406 (2016)\n[2] DJ Huggins “Quantifyi
 ng the Entropy of Binding for Water Molecules\nin Protein Cavities by Comp
 uting Correlations” – Biophysical Journal\n108\, 928-936 (2015)\n[3] S
  Vukovic\, PE Brennan\, DJ Huggins “Exploring the Role of Water in\nMole
 cular Recognition: Predicting Protein Ligandability Using a\nCombinatorial
  Search of Surface Hydration Sites”– Journal of Physics:\nCondensed Ma
 tter (2016)\n
LOCATION:TCM Seminar room\, 530 Mott building
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