(316f) Protein Dynamics in the Unfolded State with Optimized All-Atom Protein Models

A significant fraction, more than 1/3^rd, of the eukaryotic proteins are partially or completely disordered under physiological conditions. Molecular simulations serve as an ideal tool for atomic level characterization of disordered proteins as experimental characterization can be challenging due to their lack of a single fixed conformation. However, a frequently raised concern in all-atom molecular simulations is that unfolded/disordered proteins being too collapsed as compared to the experiments, suggesting that proteins are insufficiently well solvated in simulations using state-of-the-art force fields. Recently developed models with the use of a more accurate water model and with more balanced protein-water interactions address this issue and produce equilibrium dimensions closer to their experimental values. One major point that remained to be addressed is the protein conformational dynamics in the disordered states. One fundamental dynamic event in unfolded peptides is the residual contact formation. Here, we study the rates of end-to-end contact formation in model unfolded peptides), Cys-(Ala-Gly-Gln)_n-Trp, of different lengths (n ranging from 1 to 6), for which experimental tryptophan quenching data are also available. We calculate the tryptophan quenching rates and lifetimes of these peptides using Amber03*/TIP3P (1), Amber03w/TIP4P2005 (2), and Amber03ws/TIP4P2005 (3) protein/water force fields in several microsecond long molecular dynamics simulations. Based on the direct comparison of quenching rates and lifetimes between simulation and experiment, we find that Amber03ws/TIP4P2005 is near optimal for quantitative prediction of both diffusion-limited and reaction-limited rates of contact formation. Whereas simulations with Amber03*/TIP3P provide estimates that are at odd with the experimental values. This suggests that the newer optimized proteins force fields not only improve the equilibrium structural properties of disordered proteins, but can also be used for quantitative understanding of conformational dynamics.

1. Best, Robert B., and Gerhard Hummer. "Optimized molecular dynamics force fields applied to the helix−coil transition of polypeptides." J. Phys. Chem. B 113.26 (2009): 9004-9015.

2. Best, Robert B., and Jeetain Mittal. "Protein simulations with an optimized water model: cooperative helix formation and temperature-induced unfolded state collapse." J. Phys. Chem. B 114.46 (2010): 14916-14923.

3. Best, Robert B., Wenwei Zheng, and Jeetain Mittal. "Balanced Protein–Water Interactions Improve Properties of Disordered Proteins and Non-Specific Protein Association." J. Chem. Theory Comput. 10.11 (2014): 5113-5124.