Molecular simulations provide a means of studying the behavior of atoms and molecules in solution and can yield thermodynamic properties of the system such as its free energy. Ultimately, free energy calculations based on these simulations may guide pharmaceutical drug discoveries. However, sampling problems remain a substantial challenge. Here, we focus on binding free energy calculations based on molecular dynamics in a model binding site (T4 Lysozyme L99A/M102Q) with both enhanced and traditional approaches, which has proven challenging, but tractable. We compare the efficiency of enhanced sampling methods based on expanded ensemble simulations with a more traditional approach involving orientational decomposition. In the expanded ensemble approach, a single simulation spans all potential ligand binding modes, while in the orientational decomposition approach, different metastable binding modes require separate simulations. This work will help improve the efficiency of binding free energy calculations for discovery applications.

Improving the efficiency of ligand binding free energy calculations in a polar model site

243rd National Meeting (2012)

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