Prediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations

Laura Orellana (), Ozge Yoluk, Oliver Carrillo, Modesto Orozco and Erik Lindahl
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Laura Orellana: KTH Royal Institute of Technology
Ozge Yoluk: KTH Royal Institute of Technology
Oliver Carrillo: Scuola Normale Superiore de Pisa
Modesto Orozco: Joint BSC-IRB Research Program in Computational Biology, Institute for Research in Biomedicine (IRB) Barcelona
Erik Lindahl: KTH Royal Institute of Technology

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12575

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