Accurate Structure Prediction for Protein Loops Based on Molecular Dynamics Simulations with RSFF2C

Protein loops, connecting the α-helices and β-strands, are involved in many important biological processes. However, due to their conformational flexibility, it is still challenging to accurately determine three-dimensional (3D) structures of long loops experimentally and computationally. Herein, we present a systematic study of the protein loop structure prediction via a total of ∼850 μs molecular dynamics (MD) simulations. For a set of 15 long (10-16 residues) and solvent-exposed loops, we first evaluated the performance of four state-of-the-art loop modeling algorithms, DaReUS-Loop, Sphinx, Rosetta-NGK, and MODELLER, on each loop, and none of them could accurately predict the structures for most loops. Then, temperature replica exchange molecular dynamics (REMD) simulations were conducted with three recent force fields, RSFF2C with TIP3P water model, CHARMM36m with CHARMM-modified TIP3P, and AMBER ff19SB with OPC. We found that our recently developed residue-specific force field RSFF2C performed the best and successfully predicted 12 out of 15 loops with a root-mean-square deviation (RMSD) < 1.5 Å. As an alternative with lower computational cost, normal MD simulations at high temperatures (380, 500, and 620 K) were investigated. Temperature-dependent performance was observed for each force field, and, for RSFF2C+TIP3P, we found that three independent 100-ns MD simulations at 500 K gave comparable results with REMD simulations. These results suggest that MD simulations, especially with enhanced sampling techniques such as replica exchange, with the RSFF2C force field could be useful for accurate loop structure prediction.