Multiscale modeling of protein conformational dynamics

Computer simulations are becomming an inevitable tool for describing the dynamics and functions of biological macromolecules. We aim to provide new methodological solution for investigating principles of ion signaling and molecular transport in membrane proteins in selected protein systems. In particular, our goal is to provide computational tools for understanding of how observable macromolecular processes, carried out over a wide range of temporal scales, arise from molecular scale events which requires a combined use of different simulation and theoretical approaches as well as careful experimental validation. We will develop new simulation strategies to characterize thermodynamics and kinetics of biological processes involving conformational changes of proteins on the ms-ms time scale. Here we use two approaches, i) generalized Langevin equation (GLE) formalism and ii) metadynamics applied to various generalized coordinates / collective variables, which we derive from atomistic MD simulations in the known equilibrium conformational states using principal component analysis (PCA). In order to identify pathways along which energy transport takes place in proteins we analyze the coupling of the internal vibrational modes given as PCA modes and corresponding energy diffusion between them. Our tools will be applied App1) to study of dynamical switching between conformations of CaM, stimulated by different calcium load, electromagnetic pulses as well as by binding of target peptides and App2) to obtain insights in principles of water transport in sodium-glucose cotransporters (SGLT), The former system will be used for validation of the simulation results obtained by the novel approach with a direct experimental data from the pump-probe experiments.