Proteins are �molecular machines� that need to change shape and visit many conformational states to perform their function. To understand biomolecular mechanisms, it is necessary to have detailed knowledge about all those conformational states as well as the reaction pathway connecting them. Here, we present two protein systems that are known to undergo large conformational transitions.  The first is the tyrosine kinase c-Src. The catalytic activity of the kinase is tightly regulated through phosphorylation and conformational changes in multiple domains, in order to maintain normal cellular signal transductions. To understand the regulations of c-Src kinase, we have studied the kinase in the absence and presence of the regulatory apparatus. The second system is the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA).  Detailed structural studies of the pump under different conditions provided analogues of various intermediates in the reaction cycle and revealed important changes in the tertiary structure of the protein both in the cytoplasmic and in the transmembrane parts, but the pathways of the ions to and from the transmembrane binding sites during the conformational transitions are not understood.  The size of these systems range from  ?45,000 to ~291,000 atoms and the time-scale involved in the large scale motions prohibit the use of brute-force unbiased simulations to obtain statistically meaningful information.  To circumvent this challenge, the string method with swarms-of-trajectories is used to discover the optimal minimum free energy path between the two end-states.

Application of the string method to map conformational transitions in large biomolecular systems

247th National Meeting (2014)

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