title: Molecular Dynamics Simulations of Intrinsically Disordered Proteins: Force Field Evaluation and Comparison with Experiment.
abstract: An increasing number of studies using molecular dynamics (MD) simulations of unfolded and intrinsically disordered proteins (IDPs) suggest that current force fields sample conformations that are overly collapsed. Here, we study the applicability of several state-of-the-art MD force fields, of the AMBER and GROMOS variety, for the simulation of Histatin 5, a short (24 residues) cationic salivary IDP with antimicrobial and antifungal properties. The quality of the simulations is assessed in three complementary analyses: (i) protein shape and size comparison with recent experimental small-angle X-ray scattering data; (ii) secondary structure prediction; (iii) energy landscape exploration and conformational class analysis. Our results show that, indeed, standard force fields sample conformations that are too compact, being systematically unable to reproduce experimental evidence such as the scattering function, the shape of the protein as compared with the Kratky plot, and intrapeptide distances obtained through the pair distance distribution function, p(r). The consistency of this deviation suggests that the problem is not mainly due to protein-protein or water-water interactions, whose parametrization varies the most between force fields and water models. In fact, as originally proposed in [ Best et al. J. Chem. Theory Comput. 2014, 10, 5113 - 5124.], balanced protein-water interactions may be the key to solving this problem. Our simulations using this approach produce results in very good agreement with experiment.
authors.affiliation: Division of Theoretical Chemistry, Lund University , Post Office Box 124, S-221 00 Lund, Sweden.
authors.forename: João
authors.initials: J
authors.lastname: Henriques
authors.affiliation: Division of Theoretical Chemistry, Lund University , Post Office Box 124, S-221 00 Lund, Sweden.
authors.forename: Carolina
authors.initials: C
authors.lastname: Cragnell
authors.affiliation: Division of Theoretical Chemistry, Lund University , Post Office Box 124, S-221 00 Lund, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Skepö
mesh_terms: D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
chemical_list: D064267:Intrinsically Disordered Proteins