title: The Application of Ligand-Mapping Molecular Dynamics Simulations to the Rational Design of Peptidic Modulators of Protein-Protein Interactions.
abstract: A computational ligand-mapping approach to detect protein surface pockets that interact with hydrophobic moieties is presented. In this method, we incorporated benzene molecules into explicit solvent molecular dynamics simulations of various protein targets. The benzene molecules successfully identified the binding locations of hydrophobic hot-spot residues and all-hydrocarbon cross-links from known peptidic ligands. They also unveiled cryptic binding sites that are occluded by side chains and the protein backbone. Our results demonstrate that ligand-mapping molecular dynamics simulations hold immense promise to guide the rational design of peptidic modulators of protein-protein interactions, including that of stapled peptides, which show promise as an exciting new class of cell-penetrating therapeutic molecules.
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.|Bioinformatics Institute (A*STAR) , 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
authors.forename: Yaw Sing
authors.initials: YS
authors.lastname: Tan
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Abell
authors.affiliation: Bioinformatics Institute (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: D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001554:Benzene / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D010455:Peptides; D012997:Solvents; D014867:Water; D064096:Aurora Kinase A; D001554:Benzene