Molecular Dynamics and Calcium Binding Studies on Troponin C

Abstract

Troponin C (TnC) is part of the myofilament complex in both cardiac and skeletal muscle cells. It initiates myofilament contraction upon calcium binding. Here we focus on elucidating the dynamics of the cardiac regulatory domain of TnC in response to calcium as well as troponin I (TnI) binding. Both classical and accelerated molecular dynamics simulations are performed on an apo, a calcium-bound and a calcium-TnI-bound system. Conformational sampling between the two simulation methods is compared. Using a principle component analysis the conformations sampled by the different system are compared. NMR order parameters and chemical shifts are calculated based on the simulations. Agreement with experimental observables suggests that a substantial amount of the protein’s native dynamics is sampled by the simulations. Brownian dynamics simulations of calcium association with TnC on representative structures from the molecular dynamics simulations diffusion limited calcium association rates in agreement with experimental measurements. The gating regime for calcium association is investigated using Brownian dynamics simulations on representative intermediate structures.