Conformational Sampling of Maltose-Transporter Components in Cartesian Collective Variables Is Governed by the Low-Frequency Normal Modes

We have studied large-scale conformational transitions in the maltose-binding protein and the nucleotide binding domains of a maltose-transporter using enhanced conformational sampling in Cartesian collective variables with temperature-accelerated molecular dynamics (TAMD) and C_α-based elastic network normal-mode analysis. Significantly, every functional displacement in the TAMD-generated pathways of each protein could be rationalized via a single low-frequency soft mode, whereas a combination of two to three low-frequency modes was found to describe the entire conformational change, suggesting that collective functional movement in TAMD trajectories is facilitated by the intrinsically accessible low-frequency normal modes. By applying a harmonic potential to facilitate functional motion in TAMD simulations, we also provide a recipe to reproducibly generate structural transitions in both proteins, which can be used to characterize large-scale conformational changes in other biomolecules