title: Rational optimization of conformational effects induced by hydrocarbon staples in peptides and their binding interfaces.
abstract: eIF4E is frequently over-expressed in different cancers and causes increased translation of oncogenic proteins via deregulated cap-dependent translation. Inhibitors of the eIF4E:eIF4G interactions represent an approach that would normalize cap-dependent translation. Stapled peptides represent an emerging class of therapeutics that can target protein: protein interactions. We present here molecular dynamics simulations for a set of rationally designed stapled peptides in solution and in complex with eIF4E, supported with biophysical and crystallographic data. Clustering of the simulated structures revealed the favoured conformational states of the stapled peptides in their bound or free forms in solution. Identifying these populations has allowed us to design peptides with improved affinities by introducing mutations into the peptide sequence to alter their conformational distributions. These studies emphasise the effects that engineered mutations have on the conformations of free and bound peptides, and illustrate that both states must be considered in efforts to attain high affinity binding.
authors: 1] Bioinformatics Institute, A*STAR (Agency for Science, Technology and Research), 30 Biopolis Street, #07-01 Matrix, Singapore 138671 [2].
authors: Dilraj
authors: D
authors: Lama
authors: 1] p53 Laboratory, A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-04/05, Neuros/Immunos, Singapore 138648 [2].
authors: Soo T
authors: ST
authors: Quah
authors: 1] Bioinformatics Institute, A*STAR (Agency for Science, Technology and Research), 30 Biopolis Street, #07-01 Matrix, Singapore 138671 [2] Department of Biological sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543 [3] School of Biological sciences, Nanyang Technological University, 50 Nanyang Drive, Singapore 637551.
authors: Chandra S
authors: CS
authors: Verma
authors: Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 16875.
authors: Rajamani
authors: R
authors: Lakshminarayanan
authors: Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 16875.
authors: Roger W
authors: RW
authors: Beuerman
authors: p53 Laboratory, A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-04/05, Neuros/Immunos, Singapore 138648.
authors: David P
authors: DP
authors: Lane
authors: p53 Laboratory, A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-04/05, Neuros/Immunos, Singapore 138648.
authors: Christopher J
authors: CJ
authors: Brown
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry / Q000378:metabolism; D006838:Hydrocarbons / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D015203:Reproducibility of Results
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D006838:Hydrocarbons; D010455:Peptides