title: Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design.
abstract: Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated. Here, we report the use of benzenes as probe molecules in ligand-mapping MD (LMMD) simulations to predict the existence of two novel binding sites on the surface of the oncoprotein MDM2. One of them was serendipitously confirmed by biophysical assays and X-ray crystallography to be important for the binding of a new family of hydrocarbon stapled peptides that were specifically designed to target the other putative site. These results highlight the predictive power of LMMD and suggest that predictions derived from LMMD simulations can serve as a reliable basis for the identification of novel ligand binding sites in structure-based drug design.
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR) , 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
authors.forename: Yaw Sing
authors.initials: YS
authors.lastname: Tan
authors.affiliation: Northern Institute for Cancer Research, Newcastle University , Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.
authors.forename: Judith
authors.initials: J
authors.lastname: Reeks
authors.affiliation: p53 Laboratory, A*STAR , 8A Biomedical Grove, #06-04/05 Neuros/Immunos, Singapore 138648.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Brown
authors.affiliation: p53 Laboratory, A*STAR , 8A Biomedical Grove, #06-04/05 Neuros/Immunos, Singapore 138648.
authors.forename: Dawn
authors.initials: D
authors.lastname: Thean
authors.affiliation: p53 Laboratory, A*STAR , 8A Biomedical Grove, #06-04/05 Neuros/Immunos, Singapore 138648.
authors.forename: Fernando Jose
authors.initials: FJ
authors.lastname: Ferrer Gago
authors.affiliation: Institute of Chemical & Engineering Sciences, A*STAR , 8 Biomedical Grove, #07-01 Neuros, Singapore 138665.
authors.forename: Tsz Ying
authors.initials: TY
authors.lastname: Yuen
authors.affiliation: Singapore Eye Research Institute , 11 Third Hospital Avenue, Singapore 168751.
authors.forename: Eunice Tze Leng
authors.initials: ET
authors.lastname: Goh
authors.affiliation: p53 Laboratory, A*STAR , 8A Biomedical Grove, #06-04/05 Neuros/Immunos, Singapore 138648.
authors.forename: Xue Er Cheryl
authors.initials: XE
authors.lastname: Lee
authors.affiliation: Northern Institute for Cancer Research, Newcastle University , Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Jennings
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR) , 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Joseph
authors.affiliation: Singapore Eye Research Institute , 11 Third Hospital Avenue, Singapore 168751.
authors.forename: Rajamani
authors.initials: R
authors.lastname: Lakshminarayanan
authors.affiliation: p53 Laboratory, A*STAR , 8A Biomedical Grove, #06-04/05 Neuros/Immunos, Singapore 138648.
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.affiliation: Northern Institute for Cancer Research, Newcastle University , Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR) , 30 Biopolis Street, #07-01 Matrix, Singapore 138671.|Department of Biological Sciences, National University of Singapore , 14 Science Drive 4, Singapore 117543.|School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551.
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
mesh_terms: D001554:Benzene / Q000737:chemistry*; D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding
chemical_list: D008024:Ligands; D001554:Benzene