Coarse-grained Gö-model Simulation of Villin: Understanding the Folding Mechanism

Every biological protein has a specific function. Protein folding is the process by which a protein structure assumes its functional shape or conformation. Thus, studies on protein folding have been very essential and useful to understand the various intricacies in the function of a protein. To understand the folding mechanism, a 36 residue protein called ‘Villin’ (PDB ID -1VII) has been studied in silico in this research work. Computational methods have been used to determine the secondary structure of the protein while the process of folding happens. Coarse grained molecular dynamics has been used with GROMACS, so as to get a faster chemical simulation of the Villin molecule. The molecule was simulated at various temperatures with the same energy functions. Since Go model was used for the simulations, a reduced Kelvin temperature is used as most of the unwanted bonds are removed. Simulations were done for 30 different temperatures, thus creating a different protein folding trajectory for each temperature. Then, for each of the temperatures, RMSD and native contact Q values were found out by using appropriate commands. These values were plotted along with the Mean Q and Mean RMSD values to find out the exact temperature where there is equilibrium between folded and unfolded regions. This is found through the inflexion point in the plots. This temperature was found to be 116 rK (Reduced Kelvin). Now, at this temperature, we needed the time-steps where the actual transition occurs. This was found out by taking the Q values between 0.35 and 0.65. Therefore the time steps where the protein folding transition from unfolded to folded and vice versa occurred were computed. This data was then used to calculate the trajectories at those time steps. The trajectories were then used to compute the secondary structure (DSSP) using a software called STRIDE. Contact maps and Ramachandran plots were also computed for the required transitional folded paths. Therefore this thesis gives all the relevant information about the folding process in Villin molecule especially the secondary structure and gives an insight about the structural analysis in the intermediate regions of protein folding.

Keywords: Coarse grained molecule, molecular dynamics, villin molecule, GROMACS, STRIDE, contact map and Ramachandran plot.

Karplus M: Biopolymers 2003, 68:350-358.

Schleif R: Methods Enzymol 2004, 383:28-47.

Levitt M. J Mol Biol 1976, 104:59-107.

Ueeda Y, Taketomi H, GoN: Biopolymers 1978, 17:1531-1548.

Zhang Z, Shi Y, Liu H: Biophys J 2003, 84:3583-3593. ENM is used to compute the principal modes along a full-atom MD trajectory and amplify them to better explore the phase space. The method is applied to T4 lysozyme and to the refolding of an S-peptide analog.

Bryngelson JD, Wolynes PG: Proc Natl Acad Sci USA 1987, 84:7524-7528.

Leopold PE, Montal M, Onuchic JN: Proc Natl Acad Sci USA 1992, 89:8721-8725.