title: Toward a predictive understanding of slow methyl group dynamics in proteins.
abstract: The development of the most recent generation of molecular mechanics force fields promises an increasingly predictive understanding of the protein dynamics-function relationship. Based on extensive validation against various types of experimental data, the AMBER force field ff99SB was benchmarked in recent years as a favorable force field for protein simulations. Recent improvements of the side chain and backbone potentials, made by different groups, led to the ff99SB-ILDN and ff99SBnmr1 force fields, respectively. The combination of these potentials into a unified force field, termed ff99SBnmr1-ILDN, was used in this study to perform a microsecond time scale molecular dynamics simulation of free ubiquitin in explicit solvent for validation against an extensive set of experimental NMR methyl group residual dipolar couplings. Our results show a high level of consistency between the experimental data and the values predicted from the molecular dynamics trajectory reflecting a systematically improved performance of ff99SBnmr1-ILDN over the original ff99SB force field. Moreover, the unconstrained ff99SBnmr1-ILDN MD ensemble achieves a similar level of agreement as the recently introduced EROS ensemble, which was constructed based on a large body of NMR data as constraints, including the methyl residual dipolar couplings. This suggests that ff99SBnmr1-ILDN provides a high-quality representation of the motions of methyl-bearing protein side chains, which are sensitive probes of protein-protein and protein-ligand interactions.
authors.affiliation: Department of Chemistry and Biochemistry, and National High Magnetic Field Laboratory, Florida State University, Tallahassee, Florida, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Long
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Li
authors.forename: Korvin F A
authors.initials: KF
authors.lastname: Walter
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.forename: Rafael
authors.initials: R
authors.lastname: Brüschweiler
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008697:Methane / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011506:Proteins / Q000737:chemistry*; D012984:Software; D013997:Time Factors; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D000596:Amino Acids; D011506:Proteins; D025801:Ubiquitin; D008697:Methane