期刊
JOURNAL OF PHYSICAL CHEMISTRY B
卷 125, 期 11, 页码 2898-2909出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.0c11600
关键词
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资金
- HPCI System Research project [hp200153]
- MEXT as Program for Promoting Research on the Supercomputer Fugaku (Biomolecular dynamics in a living cell/MD-driven Precision Medicine)
- MEXT/KAKENHI [19H05645, 20K15737]
- RIKEN Pioneering Research Projects (Dynamic Structural Biology/Glycolipidologue Initiative)
- Grants-in-Aid for Scientific Research [20K15737] Funding Source: KAKEN
The study developed an enhanced sampling scheme for multidomain proteins and applied it to investigate the coupling between conformational changes and ligand binding in ribose-binding protein. The results showed a molecular mechanism involving conformational selection and induced fit during the open-to-closed transition in the protein.
Conformational changes of proteins upon ligand binding are usually explained in terms of several mechanisms including the induced fit, conformational selection, or their mixtures. Due to the slow time scales, conventional molecular dynamics (cMD) simulations based on the atomistic models cannot easily simulate the open-to-closed conformational transition in proteins. In our previous study, we have developed an enhanced sampling scheme (generalized replica exchange with solute tempering selected surface charged residues: gREST_SSCR) for multidomain proteins and applied it to ligand-mediated conformational changes in the G134R mutant of ribose-binding protein (RBPG134R) in solution. The free-energy landscape (FEL) of RBPG134R in the presence of a ribose at the binding site included the open and closed states and two intermediates, open-like and closed-like forms. Only the open and open-like forms existed in the FEL without a ribose. In the current study, the coupling between the conformational changes and ligand binding is further investigated using coarse-grained MD, multiple atomistic cMD, and free-energy calculations. The ribose is easily dissociated from the binding site of wild-type RBP and RBPG134R in the cMD simulations starting from the open and open-like forms. In contrast, it is stable at the binding site in the simulations from the closed and closed-like forms. The free-energy calculations provide the binding affinities of different structures, supporting the results of cMD simulations. Importantly, cMD simulations from the closed-like structures reveal transitions toward the closed one in the presence of a bound ribose. On the basis of the computational results, we propose a molecular mechanism in which conformational selection and induced fit happen in the first and second halves of the open-to-closed transition in RBP, respectively.
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