Abstract: Protein folding is an important problem that is attracting scientists from a wide range of disciplines. However, after decades of studies by both experimental and theoretical methods, we are still on the way of achieving a clear understanding of the folding mechanism even for the small, single domain peptides. One of the major challenges comes from the gap between the experimental and the theoretical studies.We proposed a computational protocol of simulating the T-jump peptide unfolding experiments and the related transient IR and 2DIR spectra based on the Markov State Model (MSM) and Nonlinear Exciton Propagation (NEP) methods. MSMs partition the conformation space into a set of non-overlapping metastable states, and we can calculate spectra signal for each of these states using NEP method. Thus the overall spectroscopic observable for a given system is simply the sum of spectra of different metastable states weighted by their populations.
We show that results from MSMs constructed from a large number of simulations have a much better agreement with the equilibrium experimental 2DIR spectra compared to that generated from straightforward MD simulations starting from the folded state.
This indicates that a sufficient sampling of important relevant conformational states is critical for calculating the accurate spectroscopic observables. MSMs are also capable of simulating the unfolding relaxation dynamics upon the temperature jump. The agreement of the simulation using MSMs and NEP with the experiment not only provides a justification for our protocol, but also provides the physical insight underlying the spectroscopic observables. The protocol we developed has the potential to be extended to simulate a wide range of fast triggering plus optical detection experiments for biomolecules.