(476g) Free Energy Landscape with Experiment Directed Simulations and Enhanced Sampling

Free Energy Surface calculations for protein folding is a daunting challenge in Molecular Dynamics (MD) without any enhanced sampling or biasing techniques. Due to large energy barriers between local and global minima, molecules may be trapped in local minima during regular MD, which is called a sampling issue. To overcome this issue, enhanced sampling techniques, such as, parallel tempering well-tempered ensemble (PT-WTE) can be used in protein simulations. PT-WTE is a multiple replica simulation running at different temperatures and swapping conformations between replicas by forcing the simulation to visit states that have not been explored yet. Simulations can be further modified to match some experimental bias. To improve the agreement between simulations and experiments, simulations can be biased with Experiment Directed Simulations (EDS). EDS is a single replica biasing technique that converges the ensemble averages of collective variables in a simulation and experiments by using maximum entropy method. As a model system for proteins, GYG peptide’s free energy surface was predicted by biasing the simulations with EDS in order to match experimental chemical shifts and by applying PT-WTE. EDS has shown compelling improvement in predicting free energy surface and efficiently sampled global minima with enhanced sampling.