2026-04-17T07:34:35Zhttps://recercat.cat/oai/request
oai:recercat.cat:2445/1793252025-12-05T14:10:46Zcom_2072_1057col_2072_478815col_2072_478917
RECERCAT author Juárez-Jiménez, Jordi author Gupta, Arun A. author Karunanithy, Gogulan author Mey, Antonia S. J. S. author Georgiou, Charis author Ioannidis, Harris author De Simone, Alessio author Barlow, Paul N. author Hulme, Alison N. author Walkinshaw, Malcolm D. author Baldwin, Andrew J. author Michel, Julien 2021-07-22T11:00:40Z2021-07-22T11:00:40Z2020-01-152021-07-22T11:00:40Z Proteins need to interconvert between many conformations in order to function, many of which are formed transiently, and sparsely populated. Particularly when the lifetimes of these states approach the millisecond timescale, identifying the relevant structures and the mechanism by which they interconvert remains a tremendous challenge. Here we introduce a novel combination of accelerated MD (aMD) simulations and Markov state modelling (MSM) to explore these 'excited' conformational states. Applying this to the highly dynamic protein CypA, a protein involved in immune response and associated with HIV infection, we identify five principally populated conformational states and the atomistic mechanism by which they interconvert. A rational design strategy predicted that the mutant D66A should stabilise the minor conformations and substantially alter the dynamics, whereas the similar mutant H70A should leave the landscape broadly unchanged. These predictions are confirmed using CPMG and R1ρ solution state NMR measurements. By efficiently exploring functionally relevant, but sparsely populated conformations with millisecond lifetimes in silico, our aMD/MSM method has tremendous promise for the design of dynamic protein free energy landscapes for both protein engineering and drug discovery. cc-by (c) Juárez-Jiménez et al., 2020 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Proteïnes Disseny de medicaments Compostos heterocíclics Compostos orgànics Proteins Drug design Heterocyclic compounds Organic compounds Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion