Publication Category: Binding Free Energies

  • Rigorous Free Energy Simulations in Virtual Screening

    Journal of Chemical Information and Modeling 60.9 (2020): 4153-4169.

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    Virtual high throughput screening (vHTS) in drug discovery is a powerful approach to identify hits: when applied successfully, it can be much faster and cheaper than experimental high-throughput screening approaches. However, mainstream vHTS tools have significant limitations: ligand-based methods depend on knowledge of existing chemical matter, while structure-based tools such as docking involve significant approximations

  • Improved Alchemical Free Energy Calculations with Optimized Smoothstep Softcore Potentials

    Journal of Chemical Theory and Computation 16.9 (2020): 5512-5525.

    Progress in the development of GPU-accelerated free energy simulation software has enabled practical applications on complex biological systems and fueled efforts to develop more accurate and robust predictive methods. In particular, this work re-examines concerted (a.k.a., single-step or unified) alchemical transformations com- monly used in the prediction of hydration and relative binding free energies (RBFE).

  • Optimal Measurement Network of Pairwise Differences

    Journal of chemical information and modeling 59.11 (2019): 4720-4728.

    When both the difference between two quantities and their individual values can be measured or computationally predicted, multiple quantities can be determined from the measurements or predictions of select individual quantities and select pairwise differences. These measurements and predictions form a network connecting the quantities through their differences. Here, I analyze the optimization of such

  • Relative Binding Free Energy Calculations in Drug Discovery: Recent Advances and Practical Considerations

    Journal of chemical information and modeling 57.12 (2017): 2911-2937.

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    Accurate in silico prediction of protein–ligand binding affinities has been a primary objective of structure-based drug design for decades due to the putative value it would bring to the drug discovery process. However, computational methods have historically failed to deliver value in real-world drug discovery applications due to a variety of scientific, technical, and practical challenges. Recently,

  • Chemical Basis for the Recognition of Trimethyllysine by Epigenetic Reader Proteins

    Nature communications 6.1 (2015): 1-12.

    A large number of structurally diverse epigenetic reader proteins specifically recognize methylated lysine residues on histone proteins. Here we describe comparative thermodynamic, structural and computational studies on recognition of the positively charged natural trimethyllysine and its neutral analogues by reader proteins. This work provides experimental and theoretical evidence that reader proteins predominantly recognize trimethyllysine via