Reconstruction of the src-SH3 Protein Domain Transition State Ensemble using Multiscale Molecular Dynamics Simulations

Is there an en route folding intermediate for cold shock proteins?

“…The total energy of any given conformation is calculated as the sum of all pairwise energies for nonlocal atoms. Discrete molecular dynamics with constant temperature 43,51 is used in both thermodynamic sampling and the studies of folding kinetics. As shown in Figure 1, residues 2-10, 14-19, 26-29, 44-53, and 58-66 are defined as strands b1-b5, respectively.…”

“…Although a knowledge-based force field has been used to fold several helical proteins succesfully, 34 it is still very challenging to fold b-proteins. Other than physical and empirical force fields, structure-centric Go-like models have been widely used to study protein folding mechanisms, [35][36][37][38][39][40][41][42][43][44][45] especially when there are no other suitable force fields available. Despite the simplicity and wellknown unphysical aspects, Go-like models have been used, with some success, to study folding dynamics 35,[37][38][39][40][41][42]44,45 and predict folding rates 46 as it is widely assumed that the folding mechanism is mainly determined by a protein's native structure.…”

Protein folding: Then and now

“…Feig et al developed a multi-scale modeling tool set, MMTSB [37], which integrates a simplified protein model with the MC simulation engine, MONSSTER [38], and the all-atom MD packages AMBER [39] or CHARMM [40]. Using a combination of CHARMM and discrete molecular dynamics (DMD) [41][42][43][44][45][46], Ding et al reconstructed the transition state ensemble of the src-SH3 protein domain through multi-scale simulations [47]. The protein folding studies can also be facilitated by sampling protein conformations near the native state.…”

“…2) [47,59,146,147]. To probe the contribution of each amino acid residue to the transition state ensemble, they calculated the Φ-values, and found high correlation between simulation and experimental Φ-values.…”

“…Identification of src SH3 residues critical to folding nucleus [47]. Monte Carlo simulations on lattice models [253] p fold as a reaction coordinate for protein folding.…”