Journal article Open Access

Unbiased Molecular Dynamics of 11 min Timescale Drug Unbinding Reveals Transition State Stabilizing Interactions

Lotz, Samuel; Dickson, Alex

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  "publisher": "Zenodo", 
  "DOI": "10.5281/zenodo.1021565", 
  "container_title": "Journal of the American Chemcial Society", 
  "language": "eng", 
  "title": "Unbiased Molecular Dynamics of 11 min Timescale Drug Unbinding Reveals Transition State Stabilizing Interactions", 
  "issued": {
    "date-parts": [
  "abstract": "<p>Abstract: Ligand (un)binding kinetics is being recognized as a determinant of drug specificity and efficacy<br>\nin an increasing number of systems. However, the calculation of kinetics and the simulation of<br>\ndrug unbinding is more difficult than computing thermodynamic quantities, such as binding free<br>\nenergies. Here we present the first full simulations of an unbinding process at pharmacologi-<br>\ncally relevant timescales (11 min), without the use of biasing forces, detailed prior knowledge, or<br>\nspecialized processors using the weighted ensemble based algorithm, WExplore. These simula-<br>\ntions show the inhibitor TPPU unbinding from its enzyme target soluble epoxide hydrolase (sEH),<br>\nwhich is a clinically relevant target that has attracted interest in kinetics optimization in order<br>\nto increase efficacy. We make use of conformation space networks (CSNs) that allow us to con-<br>\nceptualize unbinding not just as a linear process, but as a network of interconnected states that<br>\nconnect the bound and unbound states. This allows us to visualize patterns in hydrogen-bonding,<br>\nsolvation, and non-equilibrium free energies, without projection onto progress coordinates. The<br>\ntopology and layout of the network reveal multiple unbinding pathways, and other rare events,<br>\nsuch as the reversal of ligand orientation within the binding site. Furthermore, we make a pre-<br>\ndiction of the transition state ensemble, using transition path theory, and identify protein-ligand<br>\ninteractions which are stabilizing to the transition state. Additionally, we uncover trends in ligand<br>\nand binding site solvation that corroborate experimental evidence from more classical structure<br>\nkinetics relationships (SKRs) and generates new questions as to the role of drug modifications in<br>\nkinetics optimization. Finally, from the 75 observed unbinding events we calculate a residence<br>\ntime, 42 s, within 2 orders of magnitude from the experimental residence time of 11 min, which<br>\nis just outside the standard error of the calculation.</p>\n\n<p>Contents: This data repository contains the trajectories as well as the WExplore data used to keep track of cloning and merging, initial structures, clustering results, and key tables of results from the analysis. A full analysis &quot;notebook&quot; is also provided in the org-mode format.</p>", 
  "author": [
      "family": "Lotz, Samuel"
      "family": "Dickson, Alex"
  "type": "article-journal", 
  "id": "1021565"
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