Dissecting Allosteric Mutations for Antibiotic Resistance by Time-Dependent Linear Response Theory

We report a new approach that combines molecular dynamics trajectories with time-dependent linear response theory to compute the time evolution of residue fluctuation responses to force perturbations exerted at functional sites. Applying this new approach to TEM-1 beta-lactamase, we observe that the time-resolved response profiles of allosteric sites to perturbations of TEM-1 active sites are distinct from those of non-allosteric residues. Using Fourier transformations, we convert the time domain response profiles to the frequency domain and demonstrate that the frequency space representation of the perturbation response can capture the mutational behavior of each site when applied to deep sequencing mutational data. Furthermore, we show that classification models built on perturbation responses can accurately identify distal positions that regulate antibiotic resistance. These findings provide insights into the contributions of specific residues to resistance-encoded in time-resolved perturbation response behavior and highlight the importance of this new approach in identifying allosteric mutations, opening avenues for the potential characterization of additional allosteric positions without extensive computational simulations.