title: Molecular Simulations Identify Binding Poses and Approximate Affinities of Stapled α-Helical Peptides to MDM2 and MDMX.
abstract: Traditionally, computing the binding affinities of proteins to even relatively small and rigid ligands by free-energy methods has been challenging due to large computational costs and significant errors. Here, we apply a new molecular simulation acceleration method called MELD (Modeling by Employing Limited Data) to study the binding of stapled α-helical peptides to the MDM2 and MDMX proteins. We employ free-energy-based molecular dynamics simulations (MELD-MD) to identify binding poses and calculate binding affinities. Even though stapled peptides are larger and more complex than most protein ligands, the MELD-MD simulations can identify relevant binding poses and compute relative binding affinities. MELD-MD appears to be a promising method for computing the binding properties of peptide ligands with proteins.
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 Structural Chemistry, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Structural Chemistry, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
authors.forename: Sookhee N
authors.initials: SN
authors.lastname: Ha
authors.affiliation: Department of Structural Chemistry, MRL, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Boston, Massachusetts 02115, United States.
authors.forename: Tomi K
authors.initials: TK
authors.lastname: Sawyer
authors.affiliation: Department of Structural Chemistry, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Sherborne
authors.affiliation: Department of Structural Chemistry, MRL, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Frank K
authors.initials: FK
authors.lastname: Brown
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; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D010455:Peptides; D051736:Proto-Oncogene Proteins c-mdm2