title: Accelerating the Conformational Sampling of Intrinsically Disordered Proteins.
abstract: Intrinsically disordered proteins (IDPs) are a class of proteins lacking a well-defined secondary structure. Instead, they are able to attain multiple conformations, bind to multiple targets, and respond to changes in their surroundings. Functionally, IDPs have been associated with molecular recognition, cell regulation, and signal transduction. The dynamic conformational ensemble of IDPs is highly environmental and binding partner dependent, rendering the characterization of IDPs extremely challenging. Here, we compare the sampling efficiencies of conventional molecular dynamics (MD), well-tempered metadynamics (WT-META), and bias-exchange metadynamics (BE-META). The total simulation time was over 10 μs, and a 20-mer peptide derived from the Neh2 domain of the Nuclear factor erythroid 2-related factor 2 (Nrf2) protein was simulated. BE-META, with a neutral replica and seven biased replicas employing a set of seven relevant collective variables (CVs), provided the most reliable and efficient sampling. Finally, we propose a free-energy reconstruction method based on the probability distribution of the secondary structure contents. This postprocessing analysis confirms the presence of not only the β-hairpin conformation of the free Neh2 peptide but also its rare bound-state-like conformation, both of that have been experimentally observed. In addition, our simulations also predict other possible conformations to be verified with future experiments.
authors.affiliation: Department of Chemistry and Waterloo Institute for Nanotechnology, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Trang Nhu
authors.initials: TN
authors.lastname: Do
authors.affiliation: Department of Biochemistry, University of Western Ontario , 1151 Richmond Street, London, Ontario N6A 3K7, Canada.
authors.forename: Wing-Yiu
authors.initials: WY
authors.lastname: Choy
authors.affiliation: Department of Chemistry and Waterloo Institute for Nanotechnology, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Mikko
authors.initials: M
authors.lastname: Karttunen