Encounter complexes and dimensionality reduction in protein–protein association
Dima Kozakov,
Keyong Li,
David R Hall,
Dmitri Beglov,
Jiefu Zheng,
Pirooz Vakili,
Ora Schueler-Furman,
Ioannis Ch Paschalidis,
G Marius Clore,
Sandor Vajda
Affiliations
Dima Kozakov
Department of Biomedical Engineering, Boston University, Boston, United States
Keyong Li
Department of Electrical and Computer Engineering, Boston University, Boston, United States; Division of Systems Engineering, Boston University, Boston, United States
David R Hall
Department of Biomedical Engineering, Boston University, Boston, United States
Dmitri Beglov
Department of Biomedical Engineering, Boston University, Boston, United States
Jiefu Zheng
Department of Electrical and Computer Engineering, Boston University, Boston, United States
Pirooz Vakili
Division of Systems Engineering, Boston University, Boston, United States; Department of Mechanical Engineering, Boston University, Boston, United States
Ora Schueler-Furman
Department of Microbiology and Molecular Genetics, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel
Ioannis Ch Paschalidis
Department of Electrical and Computer Engineering, Boston University, Boston, United States; Division of Systems Engineering, Boston University, Boston, United States
G Marius Clore
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States
Sandor Vajda
Department of Biomedical Engineering, Boston University, Boston, United States; Department of Chemistry, Boston University, Boston, United States
An outstanding challenge has been to understand the mechanism whereby proteins associate. We report here the results of exhaustively sampling the conformational space in protein–protein association using a physics-based energy function. The agreement between experimental intermolecular paramagnetic relaxation enhancement (PRE) data and the PRE profiles calculated from the docked structures shows that the method captures both specific and non-specific encounter complexes. To explore the energy landscape in the vicinity of the native structure, the nonlinear manifold describing the relative orientation of two solid bodies is projected onto a Euclidean space in which the shape of low energy regions is studied by principal component analysis. Results show that the energy surface is canyon-like, with a smooth funnel within a two dimensional subspace capturing over 75% of the total motion. Thus, proteins tend to associate along preferred pathways, similar to sliding of a protein along DNA in the process of protein-DNA recognition.
