Abstract
As the application of computational methods in drug discovery pipelines becomes more widespread it is increasingly important to understand how reproducible their results are and how sensitive they are to choices made in simulation setup and analysis. Here we use ensemble simulation protocols, termed ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent), to investigate the sensitivity of the popular molecular mechanics Poisson-Boltzmann surface area (MMPBSA) methodology. Using the bromodomain-containing protein 4 (BRD4) system bound to a diverse set of ligands as our target, we show that robust rankings can be produced only through combining ensemble sampling with multiple trajectories and enhanced solvation via an explicit ligand hydration shell.
Highlights
The discovery and design of novel drugs is immensely expensive, with one study putting the cost of each new therapeutic molecule that reaches the clinic at US$1.8 billion[1]
Our previous work has demonstrated that molecular mechanics Poisson–Boltzmann surface area (MMPBSA) analysis of single simulations is highly unreliable with calculations initiated from the same structures varying by up to 12 kcal mol−1 for small molecules bound to HIV-1 protease and even more for flexible ligands binding to MHC16,17
We evaluate the performance of a range of ESMACS protocols in reproducing the experimental rankings across the full diverse ligand dataset, the robustness of this ranking to choices in system setup and the influence of non-standard MMPBSA components
Summary
The discovery and design of novel drugs is immensely expensive, with one study putting the cost of each new therapeutic molecule that reaches the clinic at US$1.8 billion[1]. Our previous work has demonstrated that MMPBSA analysis of single simulations is highly unreliable with calculations initiated from the same structures varying by up to 12 kcal mol−1 for small molecules bound to HIV-1 protease and even more for flexible ligands binding to MHC16,17 This served as the inspiration for our ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) protocols which use ensemble simulations that have been shown to produce results with reproducible uncertainties of less than 2 kcal mol−1 for a range of systems[9,16,18]. BRD4, in particular, has recently become something of a benchmark system for free energy calculations[15,19,20,21], including for those based on MMPBSA22
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