To understand the role of residues when a protein transitions from a folded to an unfolded state (and vice versa), I use time-lagged independent component analysis (tICA) in conjunction with enhanced sampling simulations (Metadynamics). The system used for the study was a ten residue protein, Chignolin (PDB: 5awl). From the predictions it was revealed that Proline had the most influence during the unfolding of the protein. A correlation score corresponding each adjacent pair of residues was evaluated which helped in the prediction of significance of each residue. The findings from our novel theory were consistent with results from previous research works. 

Calculating the kinetics of rare-but-important conformational transitions in complex biomolecules is a significant challenge in computational biophysics. Recently, the weighted ensemble method has gained significant popularity for its ability to compute the rates of conformational transitions in biomolecular systems using unbiased simulations. However, the progress coordinate(s) of the weighted ensemble simulation should be carefully designed to capture the slow degrees of freedom of the system. Here, we demonstrate the application of a machine learning approach, harmonic linear discriminant analysis, which builds a predictive model for class membership, to design progress coordinates for weighted ensemble simulations. We test the accuracy and efficiency of this technique for computing the kinetics of the conformational transition of alanine dipeptide and the unfolding of a small protein. 

All-atom MD simulations are used to study the passive permeation of molecules through the Stratum Corneum (SC) membrane. These molecules originate as a result of interaction of ozone (a common indoor air oxidant) and unsaturated lipid entities in the skin-oil layer. More specifically, well-tempered (WT) metadynamics is implemented to estimate the free energies of the neat Stratum Corneum system, along with the translocation of two solutes (Acetone and 6-MHO). The computed free energy profiles from WT-metadynamics are in good agreement with results from other enhanced sampling methods. Lipid-level post-simulation analysis reveal that the long simulation time scales associated with the simulations can be attributed to the internal membrane reorganization (flipping) of the cholesterol and free fatty acids. Enhanced sampling simulations of a more common bilayer. Unbiased MD simulations of the systems confirm that the lipid flips observed is a rare event and is an inherent characteristic of the Stratum Corneum model. 

Coming soon