title: Energetics and Dynamics Across the Bcl-2-Regulated Apoptotic Pathway Reveal Distinct Evolutionary Determinants of Specificity and Affinity.
abstract: Critical regulatory pathways are replete with instances of intra- and interfamily protein-protein interactions due to the pervasiveness of gene duplication throughout evolution. Discerning the specificity determinants within these systems has proven a challenging task. Here, we present an energetic analysis of the specificity determinants within the Bcl-2 family of proteins (key regulators of the intrinsic apoptotic pathway) via a total of ∼20 μs of simulation of 60 distinct protein-protein complexes. We demonstrate where affinity and specificity of protein-protein interactions arise across the family, and corroborate our conclusions with extensive experimental evidence. We identify energy and specificity hotspots that may offer valuable guidance in the design of targeted therapeutics for manipulating the protein-protein interactions within the apoptosis-regulating pathway. Moreover, we propose a conceptual framework that allows us to quantify the relationship between sequence, structure, and binding energetics. This approach may represent a general methodology for investigating other paralogous protein-protein interaction sites.
authors: Bioinformatics Institute, Agency for Science, Technology and Research (A(∗)STAR), Matrix 07-01, 30 Biopolis Street, Singapore 138671, Singapore; Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
authors: Stefan M
authors: SM
authors: Ivanov
authors: Bioinformatics Institute, Agency for Science, Technology and Research (A(∗)STAR), Matrix 07-01, 30 Biopolis Street, Singapore 138671, Singapore.
authors: Roland G
authors: RG
authors: Huber
authors: Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
authors: Jim
authors: J
authors: Warwicker
authors: Bioinformatics Institute, Agency for Science, Technology and Research (A(∗)STAR), Matrix 07-01, 30 Biopolis Street, Singapore 138671, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore. Electronic address: peterjb@bii.a-star.edu.sg.
authors: Peter J
authors: PJ
authors: Bond
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D019143:Evolution, Molecular; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2
keywords: B-cell lymphoma-2 (Bcl-2) family; BH3 peptides; affinity; apoptosis; hotspots; molecular dynamics (MD) simulations; molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations; paralogs; protein-protein interactions; specificity