Martini, LindaLindaMartiniKells, AdamAdamKellsCovino, RobertoRobertoCovinoBuchete, Nicolae-ViorelNicolae-ViorelBucheteet al.2018-01-232018-01-232017 the A2017-09-28Physical Review Xhttp://hdl.handle.net/10197/9195We present a method that enables the identification and analysis of conformational Markovian transition states from atomistic or coarse-grained molecular dynamics (MD) trajectories. Our algorithm is presented by using both analytical models and examples from MD simulations of the benchmark system helix-forming peptide Ala5, and of larger, biomedically important systems: the 15-lipoxygenase-2 enzyme (15-LOX-2), the epidermal growth factor receptor (EGFR) protein and the Mga2 fungal transcription factor. The analysis of 15-LOX-2 uses data generated exclusively from biased umbrella sampling simulations carried out at the hybrid ab initio density functional theory (DFT) quantum mechanics / molecular mechanics (QM/MM) level of theory. In all cases, our method identifies automatically the corresponding transition states and metastable conformations in a variationally optimal way, with the input of a set of relevant coordinates, by accurately reproducing the intrinsic slowest relaxation rate of each system. Our approach offers a general yet easy to implement analysis method that provides unique insight into the molecular mechanism and the rare but crucial (i.e., rate limiting) conformational pathways occurring in complex dynamical systems such as molecular trajectories.enPublished by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.Chemical physicsComputational physicsJournal Article7310.1103/PhysRevX.7.0310602017-10-17https://creativecommons.org/licenses/by-nc-nd/3.0/ie/