In collaboration with the Daggett laboratory (UW Bioengineering) and the McCulloch laboratory (UCSD), we employ molecular dynamics (MD) simulations to study atomistically detailed structure-function relationships of sarcomere proteins in silico. These simulations provide unique insight into properties of contractile proteins on length- and time-scales unattainable by traditional experimental approaches. More specifically, we are interested in using MD simulations to understand how structural changes in myosin when bound to 2-deoxy-ATP might contribute to enhanced cross-bridge formation. Additionally, we use MD simulations to understand how mutations in thin filament proteins associated with various cardiac disorders affect intramolecular interactions that are important for myofilament properties such as calcium sensitivity of force.
- Valerie Daggett, Ph.D., Department of Bioengineering, University of Washington
- Andrew McCulloch, Ph.D., Department of Bioengineering, University of California San Diego
- Lindert S, Cheng Y, Kekenes-Huskey P, Regnier M, McCammon JA. Effects of HCM cTnI mutation R145G on troponin structure and modulation by PKA phosphorylation elucidated by molecular dynamics simulations. Biophys J. 2015 Jan 20;108(2):395-407. PMCID: PMC4302190.
- Cheng Y, Lindert S, Kekenes-Huskey P, Rao VS, Solaro RJ, Rosevear PR, Amaro R, McCulloch AD, McCammon JA, Regnier M. Computational studies of the effect of the S23D/S24D troponin I mutation on cardiac troponin structural dynamics. Biophys J. 2014 Oct 7;107(7):1675-85. PMCID: PMC4190606.
- Rao V, Cheng Y, Lindert S, Wang D, Oxenford L, McCulloch AD, McCammon JA, Regnier M. PKA phosphorylation of cardiac troponin I modulates activation and relaxation kinetics of ventricular myofibrils. Biophys J. 2014 Sep 2;107(5):1196-204. PMCID: PMC4156663.
- Wang D, McCully ME, Luo Z, McMichael J, Tu AY, Daggett V, Regnier M. Structural and functional consequences of cardiac troponin C L57Q and I61Q Ca(2+)-desensitizing variants. Arch Biochem Biophys. 2013 Jul 1;535(1):68-75. PMCID: PMC3657564.
- Wang D, Robertson IM, Li MX, McCully ME, Crane ML, Luo Z, Tu AY, Daggett V, Sykes BD, Regnier M. Structural and functional consequences of the cardiac troponin C L48Q Ca(2+)-sensitizing mutation. Biochemistry. 2012 Jun 5;51(22):4473-87. PMCID: PMC3437384.