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Article

Exploring Large Domain Motions in Proteins Using Atomistic Molecular Dynamics with Enhanced Conformational Sampling

by 1 and 1,2,3,*
1
RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
2
RIKEN Center for Computational Science, Integrated Innovation Building 7F, 6-7-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
3
RIKEN Center for Biosystems Dynamics Research, Integrated Innovation Building 7F, 6-7-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(1), 270; https://doi.org/10.3390/ijms22010270
Received: 21 November 2020 / Revised: 23 December 2020 / Accepted: 25 December 2020 / Published: 29 December 2020
Conformational transitions in multidomain proteins are essential for biological functions. The Apo conformations are typically open and flexible, while the Holo states form more compact conformations stabilized by protein-ligand interactions. Unfortunately, the atomically detailed mechanisms for such open-closed conformational changes are difficult to be accessed experimentally as well as computationally. To simulate the transitions using atomistic molecular dynamics (MD) simulations, efficient conformational sampling algorithms are required. In this work, we propose a new approach based on generalized replica-exchange with solute tempering (gREST) for exploring the open-closed conformational changes in multidomain proteins. Wherein, selected surface charged residues in a target protein are defined as the solute region in gREST simulation and the solute temperatures are different in replicas and exchanged between them to enhance the domain motions. This approach is called gREST selected surface charged residues (gREST_SSCR) and is applied to the Apo and Holo states of ribose binding protein (RBP) in solution. The conformational spaces sampled with gREST_SSCR are much wider than those with the conventional MD, sampling open-closed conformational changes while maintaining RBP domains’ stability. The free-energy landscapes of RBP in the Apo and Holo states are drawn along with twist and hinge angles of the two moving domains. The inter-domain salt-bridges that are not observed in the experimental structures are also important in the intermediate states during the conformational changes. View Full-Text
Keywords: molecular dynamics; enhanced conformational sampling algorithm; ribose binding protein; gREST_SSCR; free energy landscapes; hinge and twist angles; inter-domain salt bridges molecular dynamics; enhanced conformational sampling algorithm; ribose binding protein; gREST_SSCR; free energy landscapes; hinge and twist angles; inter-domain salt bridges
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MDPI and ACS Style

Dokainish, H.M.; Sugita, Y. Exploring Large Domain Motions in Proteins Using Atomistic Molecular Dynamics with Enhanced Conformational Sampling. Int. J. Mol. Sci. 2021, 22, 270. https://doi.org/10.3390/ijms22010270

AMA Style

Dokainish HM, Sugita Y. Exploring Large Domain Motions in Proteins Using Atomistic Molecular Dynamics with Enhanced Conformational Sampling. International Journal of Molecular Sciences. 2021; 22(1):270. https://doi.org/10.3390/ijms22010270

Chicago/Turabian Style

Dokainish, Hisham M., and Yuji Sugita. 2021. "Exploring Large Domain Motions in Proteins Using Atomistic Molecular Dynamics with Enhanced Conformational Sampling" International Journal of Molecular Sciences 22, no. 1: 270. https://doi.org/10.3390/ijms22010270

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