Metadynamics and Umbrella Sampling of Calmodulin Conformations

*** This project is a continuation of previous PURE; please do not apply unless invited by the supervisor to do so.***

Our group's research program is based-on predicting the functions of proteins whose three-dimensional structures are known using dynamical information obtained from trajectories and to foretell how the shifts in the environmental conditions will change these functions. Most folded proteins occupy multiple conformations that are close on the conformational space (CS) but are separated by high energy barriers. Computational and experimental methods determine only one or a few of these at best. Moreover, transitions between these occur on the timescales that are beyond the reach of most current computers. To further complicate matters, minor changes in environmental variables also affect the dynamics of transitions between these structures and their populations.

In the previous PURE call, the metadynamics protocol was successfully applied to navigate between the minima of the protein calmodulin. In this project we will enhance the findings to determine not only the thermodynamics of the energy surface of this protein, but also the nature of the kinetic barriers using established protocol. Selecting the collective variable is the most crucial step in these types of problems. We will combine the infrequent metadynamics method [1] with our perturb-scan-pull approach [2] and assess the success of the methodology. We will also implement umbrella sampling as an alternative method to assess our findings.

[1] D. Ray and M. Parrinell, “Kinetics from Metadynamics: Principles, Applications, and Outlook,” J. Chem. Theory Comput., J. Chem. Theory Comput., 19, 5649-5670 (2023). https://doi.org/10.1021/acs.jctc.3c00660
[2] F. Jalalypour, O. Sensoy, C. Atilgan, "Perturb-Scan-Pull: A Novel Method Facilitating Conformational Transitions in Proteins," J. Chem. Theory Comput., 16, 3825-3841(2020). https://pubs.acs.org/doi/10.1021/acs.jctc.9b01222