Dynamics of Contact Formation in Disordered Polypeptides

Abstract

Molecular simulations with reliable protein and solvent models can provide information on timescales associated with reconfiguration of unfolded/disordered proteins in aqueous solution. One fundamental dynamical timescale associated with protein unfolded state that has been measured experimentally is the rate of contact formation between a probe and a quencher. We use all-atom molecular dynamics simulations to calculate the characteristic time of contact formation in disordered peptides and how it depends on peptide length. We find that our simulations with a recently proposed protein model (Amber03ws with TIP4P2005 water model) can quantitatively capture the experimental quenching times. With our simulation data, we can also address if commonly used one-dimensional (1D) diffusion models to interpret experimental data are reliable or not. We find that the results obtained from Szabo-Schulten-Schulten theory applied to a 1D diffusion model derived from the simulation data are in remarkable agreement with directly calculated rates. We also present simulation results on dynamics associated with conformational changes in the unfolded state for many long disordered proteins and compare it with the available single-molecule FRET and NMR data. Our main finding is that modern protein force fields are capable of providing accurate information on protein dynamics in the disordered states.