Analysis of a large conformational change in the membrane protein NapA with time-lagged independent component analysis

Molecular Dynamics (MD) simulations provide an unique avenue of exploring conformational changes of proteins at atomic level resolution. However, the identification of which physical components of the protein contributes towards a conformational change has been a challenge due to inherent high dimensionality of the trajectory. Here, we apply dimensionality reduction algorithms to the MD trajectories to determine which features of the protein contribute most towards a particular conformation change. We focus on time-lagged independent component analysis (tICA), a dimensionality reduction method that discovers collective motions associated with the slowest time scales of the molecular motion. We apply tICA to the functionally critical "elevator motion" of the NapA membrane protein, a secondary active transporter that exchanges protons for sodium ions across the cell membrane. We assess different features such as the backbone dihedral angle and salt bridge distances are best suited to identify which physical structures contribute the most towards the elevator-like conformational change.