| Title | : | Pathway Heterogeneity in Protein Folding |
| Speaker | : | Animesh Kumar Singh (IITM) |
| Details | : | Tue, 19 Apr, 2016 5:00 PM @ BSB 361 |
| Abstract: | : | Understanding the dynamics of protein folding is a challenging problem in molecular biology, which started back in 1964 with Anfinsen’s Nobel Prize winning work. The complexity of folding pathways depends on multiple factors like the protein length, sequence complexity, and stability conditions. In this thesis, we investigate the pathway heterogeneity in protein folding of two fast folding proteins gpW and WW and one slow folding protein SH3 using network analysis and visualization. Specifically, we ask the following question: does the majority of the pathways starting from unfolded ensembles lead to the native conformation? To answer this, we run 10000 simulations for each protein from an unfolded state leading to the native conformation. We employ Monte Carlo simulation to generate trajectories that are sequences of microstates from an unfolded state to the native conformation. Analyzing these sequences of folding events, we see that a protein evades irrelevant conformations to fold quickly. This reduces the complexity of search in the space of microstates. While folding, the protein takes a local independent decision first followed by a global one. For visualization, to reduce the complexity even further, we take the top 1000 frequent microstates to show the complexity involved in the folding pathways. The protein gpW is the most complex among the three proteins under analysis, followed by SH3, and WW. Remarkably, a simplified network representation of trajectories captures the sequence of folding events and the complexity involved in the folding process. We use the MCL algorithm that can mark the presence of well-defined communities to show the presence of intermediate events in the network representation of the protein. However, the folding process and the number of pathways strongly differ for all three proteins. To further understand the diversity in folding pathways, we also examine them by tracking the formation of secondary structures and review the existence of single pathways as well as multiple equiprobable pathways. The results are validated on the basis of percentage of flux going through each pathway. It helps to characterize the complete folding pathways for the two slow folding proteins and one fast folding protein in terms of folding barriers and number of unique pathways. |
