title: Computed Binding of Peptides to Proteins with MELD-Accelerated Molecular Dynamics.
abstract: It has been a challenge to compute the poses and affinities for binding of peptides to proteins by molecular dynamics (MD) simulations. Such computations would be valuable for capturing the physics and the conformational freedom of the molecules, but they are currently too computationally expensive. Here we describe using MELD (Modeling Employing Limited Data)-accelerated MD for finding the binding poses and approximate relative binding free energies for flexible-peptide/protein interactions. MELD uses only weak information about the binding motif and not the detailed binding mode that is typically required by other free-energy-based methods. We apply this technique to study binding of P53-derived peptides to MDM2 and MDMX. We find that MELD finds correct poses, that the binding induces the peptide into the correct helical conformation, and that it is capable of roughly estimating relative binding affinities. This method may be useful in peptide drug discovery.
authors.affiliation: Laufer Center for Physical and Quantitative Biology, Stony Brook University , Stony Brook, New York 11794, United States.
authors.forename: Joseph A
authors.identifier: http://orcid.org/0000-0001-8550-4854
authors.initials: JA
authors.lastname: Morrone
authors.affiliation: Laufer Center for Physical and Quantitative Biology, Stony Brook University , Stony Brook, New York 11794, United States.
authors.forename: Alberto
authors.initials: A
authors.lastname: Perez
authors.affiliation: Department of Chemistry, University of Calgary , Calgary, Alberta T2N 1N4, Canada.
authors.forename: Justin
authors.initials: J
authors.lastname: MacCallum
authors.affiliation: Laufer Center for Physical and Quantitative Biology, Stony Brook University , Stony Brook, New York 11794, United States.|Department of Chemistry, Stony Brook University , Stony Brook, New York 11794, United States.|Department of Physics & Astronomy, Stony Brook University , Stony Brook, New York 11794, United States.
authors.forename: Ken A
authors.initials: KA
authors.lastname: Dill
mesh_terms: D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry
chemical_list: D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2