期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 6, 页码 2397-2402出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0908754107
关键词
molecular dynamics; protein unfolding mechanism; transition path sampling; transition state ensemble; committor analysis
资金
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Stichting Nationale Computerfaciliteiten
Understanding the dynamics of large-scale conformational changes in proteins still poses a challenge for molecular simulations. We employ transition path sampling of explicit solvent molecular dynamics trajectories to obtain atomistic insight in the reaction network of the millisecond timescale partial unfolding transition in the photocycle of the bacterial sensor photoactive yellow protein. Likelihood maximization analysis predicts the best model for the reaction coordinates of each substep as well as tentative transition states, without further simulation. We find that the unfolding of the alpha-helical region 43-51 is followed by sequential solvent exposure of both Glu46 and the chromophore. Which of these two residues is exposed first is correlated with the presence of a salt bridge that is part of the N-terminal domain. Additional molecular dynamics simulations indicate that the exposure of the chromophore does not result in a productive pathway. We discuss several possibilities for experimental validation of these predictions. Our results open the way for studying millisecond conformational changes in other medium-sized (signaling) proteins.
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