Encounter complexes and dimensionality reduction in protein-protein association.
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. DOI: http://dx.doi.org/10.7554/eLife.01370.001.
Department of Biomedical Engineering, Boston University, Boston, United States.
Dima
D
Kozakov
Keyong
K
Li
David R
DR
Hall
Dmitri
D
Beglov
Jiefu
J
Zheng
Pirooz
P
Vakili
Ora
O
Schueler-Furman
Ioannis Ch
ICh
Paschalidis
G Marius
GM
Clore
Sandor
S
Vajda
D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
D011506:Proteins
FFT sampling; encounter landscapes; protein–protein interactions