期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 5, 页码 2302-2308出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1908379117
关键词
protein dimer association/dissociation; dewetting transition; dynamical solvent effect; hydrophobic hydration; insulin dimerization
资金
- Department of Science and Technology, Government of India
- Sir J. C. Bose Fellowship
- Council of Scientific and Industrial Research, India
Water, often termed as the lubricant of life, is expected to play an active role in navigating protein dissociation-association reactions. In order to unearth the molecular details, we first compute the free-energy surface (FES) of insulin dimer dissociation employing metadynamics simulation, and then carry out analyses of insulin dimerization and dissociation using atomistic molecular-dynamics simulation in explicit water. We select two sets of initial configurations from 1) the dissociated state and 2) the transition state, and follow time evolution using several long trajectories (similar to 1-2 mu s). During the process we not only monitor configuration of protein monomers, but also the properties of water. Although the equilibrium structural properties of water between the two monomers approach bulklike characteristics at a separation distance of similar to 5 nm, the dynamics differ considerably. The complex association process is observed to be accompanied by several structural and dynamical changes of the system, such as large-scale correlated water density fluctuations, coupled conformational fluctuation of protein monomers, a dewettinglike transition with the change of intermonomeric distance R-MM from similar to 4 to similar to 2 nm, orientation of monomers and hydrophobic hydration in the monomers. A quasistable, solventshared, protein monomer pair (SSPMP) forms at around 2 nm during association process which is a local free-energy minimum having similar to 50-60% of native contacts. Simulations starting with arrangements sampled from the transition state (TS) of the dimer dissociation reveal that the final outcome depends on relative orientation of the backbone in the hotspot region.
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