title: Efficient Atomistic Simulation of Pathways and Calculation of Rate Constants for a Protein-Peptide Binding Process: Application to the MDM2 Protein and an Intrinsically Disordered p53 Peptide.
abstract: The characterization of protein binding processes - with all of the key conformational changes - has been a grand challenge in the field of biophysics. Here, we have used the weighted ensemble path sampling strategy to orchestrate molecular dynamics simulations, yielding atomistic views of protein-peptide binding pathways involving the MDM2 oncoprotein and an intrinsically disordered p53 peptide. A total of 182 independent, continuous binding pathways were generated, yielding a kon that is in good agreement with experiment. These pathways were generated in 15 days using 3500 cores of a supercomputer, substantially faster than would be possible with "brute force" simulations. Many of these pathways involve the anchoring of p53 residue F19 into the MDM2 binding cleft when forming the metastable encounter complex, indicating that F19 may be a kinetically important residue. Our study demonstrates that it is now practical to generate pathways and calculate rate constants for protein binding processes using atomistic simulation on typical computing resources.
authors.affiliation: Department of Chemistry, Drake University , Des Moines, Iowa 50311, United States.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Zwier
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Pratt
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Adelman
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Kaus
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Zuckerman
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States|Institute of Biochemistry and Biotechnology, Martin-Luther Universität Halle-Wittenberg, Halle 06120, Germany
authors.forename: Lillian T
authors.initials: LT
authors.lastname: Chong
mesh_terms: D001665:Binding Sites; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000502:physiology*; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
chemical_list: D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2