Folding Thermodynamics and Kinetics of Lambda-Repressor from All-Atom Molecular Dynamics Simulations

Abstract

The five-helix bundle lambda repressor fragment (λ6-85) is a fast-folding protein. A length of 80 residues puts it on the large end among all known fast folders, and hence its size poses a computational challenge for molecular dynamics (MD) studies. We simulated the folding of λ6-85 in explicit solvent using an all-atom model. By means of a single copy tempering method, adaptive tempering sampling, we observed folding, unfolding, and refolding of λ6-85 in a 6-microsecond long trajectory. The best root mean square deviation (RMSD) relative to the crystal structure native state arising in the trajectory was 1.8 A. Thermodynamic quantities, such as heat capacity and transition temperature of the protein, were calculated from the simulation and compared with experiment. The folding kinetics was investigated through a set of equilibrium MD simulations at different temperatures that together covered more than 100 microseconds. The protein was seen to fold into the native-like topology with RMSD relative to the crystallographic structure of less than 4 A. Folding pathway and several folding intermediates were identified through cluster analysis. The simulations suggest a new fast-folding 4-helix truncation waiting to be tested in experiment.