title: A GRID-derived water network stabilizes molecular dynamics computer simulations of a protease.
abstract: Structural water molecules are crucial for the stability and function of proteins. Recently, we presented a molecular dynamics (MD) study on blood coagulation factor Xa (fXa) to investigate the effect of water molecules on the flexibility of the protein structure. We showed that neglecting important water positions at the outset of the simulation leads to severe structural distortions during the MD simulations: A stable trajectory was obtained with a water set that was derived from all 73 X-ray structures of the protein. However, for many proteins of interest, only limited structural data is available, which precludes the merging of information from many X-ray structures. Here, we show that an in silico assembled water network, derived from molecular interaction fields generated with the GRID program, is a viable alternative to X-ray data. MD simulations with the GRID water set show a significantly improved stability over alternative setups without water or the X-ray resolved water molecules in the starting structure. The performance is comparable to a water setup derived from a recently presented clustering approach.
authors.affiliation: Computational Chemistry, Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co., KG 88397 Biberach, Germany.
authors.forename: Hannes G
authors.initials: HG
authors.lastname: Wallnoefer
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
authors.forename: Thomas
authors.initials: T
authors.lastname: Fox
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D012984:Software; D013816:Thermodynamics; D014867:Water / Q000737:chemistry* / Q000378:metabolism
chemical_list: D014867:Water; D015951:Factor Xa