Energy Landscape Theory of Protein Folding

By developing the statistical mechanical models and coarse-grained simulation techniques, we investigate the free energy surface of protein folding. Competition and selection among multiple folding pathways and multiple intermediates are clarified by drawing the multi-dimensional surface of free energy of folding processes. Hierarchical structure of the funneled energy landscape is analyzed and the principles of structural organization of systems including multi-domain proteins, protein complexes, and intrinsically disordered proteins are studied.

  • K. Itoh and M. Sasai, "Multi-dimensional theory of protein folding", J. Chem. Phys. 130: 145104_1-21 (2009).
  • K. Itoh and M. Sasai, "Cooperativity, connectivity, and folding pathways of multidomain proteins", Proc. Natl. Acad. Sci. USA 105: 13865-13870 (2008).

  • In order to investigate the process of time scales as long as milliseconds or longer, the new type of coarse-grained model is developed. Through the molecular dynamics simulations with this coarse-grained model, we investigate problems including protein complex formation, evolutionary simulation of sequence selection, and protein structure prediction.

  • T. N. Sasaki, H. Cetin, and M. Sasai, "A coarse-grained Langevin molecular dynamics approach to de novo protein structure prediction", Biochem. Biophys. Research Comm. 369: 500-506 (2008).
  • C. Nagao, T.P. Terada, T. Yomo & M. Sasai, Proc. Natl. Acad. Sci. USA 102: 18950-18955 (2005).


  • Statistical Mechanical Theory of Allosteric Transition

    The mechanism of allosteric transition is still elusive: How does the entropic change influence the transition rate? How do the non-native interactions play roles in the course of transitions? In order to elucidate the principles of allostery, we develop the new statistical mechanical model and the new coarse-grained model of transition and analyze the multi-dimensional (i.e., dynamic) energy landscapes of allosteric change. The new coarse-grained model, "Chameleon Model", developed by Dr. Terada highlights the role of localized frustrations in proteins and reveals the new aspects of protein functioning, which has not been considered in the traditional deterministic machinery picture of allostery.
  • T.P. Terada et al., in preparation
  • K. Itoh and M. Sasai, "Statistical mechanics of protein allostery: Roles of backbone and side-chain structural fluctuations", J. Chem. Phys. 134: 125102_1-18 (2011).
  • K. Itoh and M. Sasai, "Entropic mechanism of large fluctuation in allosteric transition", Proc. Natl. Acad. Sci. USA 107: 7775-7780 (2010).


  • Sliding Motion in Actomyosin Motor

    The mechanism of muscle contraction, i.e., the mechanism of actomyosion motor has been under the debate. In the traditional view, the mechanical force is generated by the myosin structural change. In this hypothesis, we have to assume that the change in the myosin conformation is in one-to-one correspondence to the ATP hydrolysis and the rate of the reversible conformational change of myosin is negligible. With the more generic assumptions on the stochastic conformational change of the flexible myosin molecule, however, we should leave from the traditional hypothesis and should try to examine the possibility of the biased Brownian motion of myosin molecule along the actin filament. We are critically examining the possibility of the biased Brownian motion by simulating the actomyosin system with the coarse-grained model.
  • M. Takano, T. P. Terada, and M. Sasai, "Unidirectional Brownian motion observed in an in silico single molecule experiment of an actomyosin motor", Proc. Natl. Acad. Sci. USA 107: 7769-7774 (2010).
  • T. P. Terada, M. Sasai, and T. Yomo, "Conformational change of actomyosin complex drives the multiple stepping movement", Proc. Natl. Acad. Sci. USA 99: 9202-9206 (2002).
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