Dr. Edina Rosta
Senior Lecturer
King's College London
Abstract
Important biological processes taking place on the millisecond to second time scales are too slow to model using unbiased atomistic simulations. To obtain free energy profiles on long time scales, enhanced sampling methods have been developed. We show that novel Markov modelling-based tools can be used to analyse biased and unbiased simulations. Using our dynamic weighted histogram analysis method (DHAM), systematic errors due to insufficient global convergence can be corrected [1]. In addition, DHAM also provides direct kinetic information on the conformational transitions intrinsic to the system. We also demonstrate that a variationally optimal kinetic coarse graining allows us to obtain Markov models, where not only metastable, but also transition states can be automatically identified [2]. Applications include analysis of molecular dynamics simulations of RAF kinases [3] and umbrella sampling quantum classical QM/MM simulations of catalytic reactions [4].
References
[1]: Rosta, E. and Hummer, G. (2015) Free Energies from Dynamic Weighted Histogram Analysis Using Unbiased Markov State Model. J. Chem. Theory Comput., 11, 276-285.
[2]: Martini, L.; Kells, A.; Covino, R.; Hummer, G.; Buchete, N-V.; Rosta, E. (2017) Variational identification of Markovian transition states, Phys. Rev. X, doi: 10.1103/PhysRevX.7.031060.
[3]: (a) Jambrina, P. G.; Bohuszewicz, O.; Buchete, N. V.; Kolch, W.; Rosta, E., Biochem. Soc. Trans. 2014, 42 (4), 784-90; (b) Jambrina, P. G.; Rauch, N.; Pilkington, R.; Rybakova, K.; Nguyen, L. K.; Kholodenko, B. N.; Buchete, N.-V.; Kolch, W.; Rosta, E., Angewandte Chemie International Edition 2016, 55 (3), 983-986.
[4]: Suardíaz, R.; Jambrina, P. G.; Masgrau, L.; González-Lafont, À.; Rosta, E.; Lluch, J. M., Understanding the Mechanism of the Hydrogen Abstraction from Arachidonic Acid Catalyzed by the Human Enzyme 15-Lipoxygenase-2. A Quantum Mechanics/Molecular Mechanics Free Energy Simulation. Journal of Chemical Theory and Computation 2016.
Video Recording
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Virtual Winter School on Computational Chemistry