dc.description.abstract | Trp-cage is a mini-protein composed of 20 residues. Here its folding is simulated in computer using the method of molecular dynamics with the aid of the software package GROMACS. Simulation was conducted in explicit solvation model and the GROMOS 96 43a1 force field was used. The parallel-tempering, or replica-exchange, algorithm was employed to enhance the efficiency of the exploration of conformational space. Folding of replicas of the peptide were simulated in twenty-six temperatures ranging from 250K to 478K are temperatures of pairs of replicas were swapped at certain time intervals according to a fixed rule. A total of 104,000 conformations were collected for analysis, representing an accumulated simulation time of 4.16 μs. A part of the present project is the construction of a distributed computing facility, called Protein@CBL, on which simulations reported here were conducted. Details on both the hardware and software aspects of Protein@CBL are described here.
All simulations began with the Trp-cage replica being in an extended state. A number of parameters measuring the folding state of the replica, including total energy and potential energy, state probability, first arrival time, radius of gyration, separation of hydrophobic and hydrophilic residues, salt bridge bond length, and heat capacity were computed. In many cases these were expressed as functions of RMSD, the rms positional deviation relative to the native conformation. The three values, RMSD ~0.70, 0.50, and 0.35 nm, with first-arrival times of 0.6, 8 and 20 ns, respectively, demarcated the folding into four regimes: extended state, molten globule, free-energy barrier, and native-like. Folding was essentially kinetic in the extended state regime, dominated by kinetics but impeded by rapid loss of entropy in the molten globule regime and largely entropic thereafter. At RMSD ~0.50 nm the hydrophilic and hydrophobic residues became cleanly separated into an outer shell and an inner core. The most native-like state had a first-arrival time of 152 ns and an RMSD of 0.23 nm. The lowest energy state given by the GROMOS force-field is probably not native-like and the average time needed to fold to a state with RMSD<0.20 nm is estimated to be 10 μs. An extended state was about 540 kJ/mol above the average potential of a molten globule and a lowest energy state was about 450 kJ/mol below. | en_US |