title: Prediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations.
abstract: Protein conformational changes are at the heart of cell functions, from signalling to ion transport. However, the transient nature of the intermediates along transition pathways hampers their experimental detection, making the underlying mechanisms elusive. Here we retrieve dynamic information on the actual transition routes from principal component analysis (PCA) of structurally-rich ensembles and, in combination with coarse-grained simulations, explore the conformational landscapes of five well-studied proteins. Modelling them as elastic networks in a hybrid elastic-network Brownian dynamics simulation (eBDIMS), we generate trajectories connecting stable end-states that spontaneously sample the crystallographic motions, predicting the structures of known intermediates along the paths. We also show that the explored non-linear routes can delimit the lowest energy passages between end-states sampled by atomistic molecular dynamics. The integrative methodology presented here provides a powerful framework to extract and expand dynamic pathway information from the Protein Data Bank, as well as to validate sampling methods in general.
authors: Department of Theoretical Physics, KTH Royal Institute of Technology, Box 1031, 171 21 Solna, Sweden.
authors: Laura
authors: 0000-0003-1927-555X
authors: L
authors: Orellana
authors: Department of Theoretical Physics, KTH Royal Institute of Technology, Box 1031, 171 21 Solna, Sweden.
authors: Ozge
authors: O
authors: Yoluk
authors: Scuola Normale Superiore de Pisa, Dipartimento di Fisica, Piazza dei Cavalieri, 7, 56126 Pisa, Italy.
authors: Oliver
authors: O
authors: Carrillo
authors: Joint BSC-IRB Research Program in Computational Biology, Institute for Research in Biomedicine (IRB) Barcelona, C/Baldiri Reixac 10, 08028 Barcelona, Spain.
authors: Modesto
authors: M
authors: Orozco
authors: Department of Theoretical Physics, KTH Royal Institute of Technology, Box 1031, 171 21 Solna, Sweden.
authors: Erik
authors: E
authors: Lindahl
mesh_terms: D000465:Algorithms; D030562:Databases, Protein; D005240:Feasibility Studies; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis / Q000379:methods*; D011487:Protein Conformation