TCBG Seminar

Using Metadynamics to Understand the Mechanism of Calmodulin/target Recognition at Atomic Detail

Dr. Giacomo Fiorin
Department of Chemistry
University of Pennsylvania
Philadelphia, PA

Thursday, November 29, 2007
2:00 pm (CT)
3269 Beckman Institute


The ability of calcium-bound calmodulin (CaM) to recognize most of its target peptides is caused by its binding to two hydrophobic residues (``anchors''): in most of the CaM complexes, these two anchors pack against the hydrophobic pockets of the CaM domains, stabilizing the CaM/peptide ``embrace''. The canonical example of these complexes, that of CaM with the myosin light chain kinase (MLCK) peptide, was studied by molecular dynamics, both unbiased and in association with the metadynamics algorithm (Laio and Parrinello, PNAS 2002). Free energies of the recognition of peptide anchors were calculated in good agreement with H/D exchange measurements, and simulations were validated by comparison with mutagenesis and NMR data (Fiorin et al, Biophys J, 2006). This study will be illustrated in detail, with emphasis on the computational setup employed and on the role of the specific system studied in the perspective of the calcium signaling cellular network.

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