title: Modeling the charge distribution at metal sites in proteins for molecular dynamics simulations.
abstract: Almost half of the proteome of living organisms is constituted of metalloproteins. Unfortunately, the ability of the current generation of molecular dynamics pairwise-additive forcefields to properly describe metal pockets is severely lacking due to the intrinsic difficulty of handling polarization and charge transfer contributions. In order to improve the description of metalloproteins, a simple reparameterization strategy is proposed herein that does not involve artificial constraints. Specifically, a non-bonded quantum mechanical-based model is used to capture the mean polarization and charge transfer contributions to the interatomic forces within the metal site. The present approach is demonstrated to provide enough accuracy to maintain the integrity of the metal pocket for a variety of metalloproteins during extended (multi-nanosecond) molecular dynamics simulations. The method enables the sampling of small conformational changes and the relaxation of local frustrations in NMR structures.
authors.affiliation: Center for Molecular Modeling and Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA. matteodp@cmm.upenn.edu
authors.forename: M
authors.initials: M
authors.lastname: Dal Peraro
authors.forename: Katrin
authors.initials: K
authors.lastname: Spiegel
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lamoureux
authors.forename: Marco
authors.initials: M
authors.lastname: De Vivo
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
mesh_terms: D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D008667:Metalloproteins / Q000737:chemistry*; D008670:Metals / Q000737:chemistry; D008958:Models, Molecular; D017510:Protein Folding
chemical_list: D008667:Metalloproteins; D008670:Metals