Abstract
The sarcoplasmic reticulum (SR) ATPase (SERCA) actively transports calcium ions across the membrane. A number of sequential steps are involved in the catalytic cycle, starting with the binding of two Ca2+ ions to the ground state (E2) to form a phosphorylated intermediate (ADP.E1P.2Ca2+). ADP dissociation is followed by the isomerization of E1P.2Ca2+ to E2P.2Ca2+ and dissociation of Ca2+, finally hydrolytic cleavage of Pi from E2P. Twenty five mutations have been identified on the Actuator (A), Phosphorylation (P) and Nucleotide binding (N) domains that have significant impact on the structure and function of Ca-ATPase (Toyoshima et al, Biochemistry (2005), 44, 8090-8100). While a lot has been studied about the relative positions of domains and the structural changes involved in the catalytic cycle, the actual kinetics and conformational transitions are yet to be explored. The main focus of this research is to study the impact of these mutations on the kinetics of reactions involving conformational changes in the catalytic cycle of SERCA. Since this required generating many sets of transitions between intermediate states, we have implemented the coarse-grained protein and lipid model (Marrink et al, JCTC(2007) 4(5), 819-834) in CHARMM. Coarse-grained models have been used to address the problem of time scales inaccessible to the all atom approach. We use Dynamic Importance Sampling (DIMS) to generate transitions between the intermediate states. Transitions are generated between each mutated open and closed conformational state in both coarse-grained and all atom model in CHARMM. A comparison of both sheds light on the kinetics and the nature of transitions involving structural changes during the opening and closing of the pump.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.