LAUSR

Pin1 enzyme is one of the peptidyl-prolyl cis/trans isomerases (PPIase), which isomerizes an omega bond of specific phospho-Serine/Threonine-Proline motifs, leading to many biological consequences. However, the isomerization mechanism has not been fully clarified yet though there are several experimental and numerical studies. For example, Tate and coworkers investigated a mutated (C113D) Pin1, and found that the isomerization rate is lower than that in the wild type [1], but it is difficult to understand the mechanism only from the experiment. Previously, Hamelberg and coworkers carried out molecular dynamics (MD) simulations of Pin1 with a model substrate, and because the isomerization process is a rare event, they used accelerated MD method [2] to enhance the sampling in configuration space. We here use temperature accelerated MD (TAMD) with several order parameters [3], and explore the free energy landscape for the isomerization process of Pin1. Combining with the string method [4], we will clarify the reaction pathways, and also examine the reaction rate using milestoning [5] or non-Markov type analysis of trajectories [6].[1] Ning Xu et al. Biochemistry, 53, 5568-5578 (2014).[2] H.A. Velazquez and D. Hamelberg, J. Phys. Chem. B 117, 11509-11517 (2013).[3] H. Fujisaki, K. Moritsugu, Y. Matsunaga, T. Morishita, L. Maragliano, Front. Bioeng. and Biotechnol. 3: 125, Doi: 10.3389/fbioe.2015.00125.[4] L. Maragliano and E. Vanden-Eijnden, Chem. Phys. Lett. 446, 182-190 (2007).[5] L. Maragliano, E. Vanden-Eijnden and B. Roux, J. Chem. Theory Comp. 5, 2589-2594 (2009).[6] E. Suarez, J.L. Adelman, and D.M. Zuckerman, J. Chem. Theor. Comput. DOI:10.1021/acs.jctc.6b00339.