Scientific Publications

Binding Free Energies

• Rigorous Free Energy Simulations in Virtual Screening

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

  Most Read

  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.

  Most ReadWidely Cited

  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…

Conformational Free Energies

• Evaluation of Conformational Changes in Diabetes-Associated Mutation in Insulin a Chain: A Molecular Dynamics Study.

  Proteins: Structure, Function, and Bioinformatics 83.4 (2015): 662-669.

  permanent neonatal-onset diabetes mellitus known as Mutant INS-gene induced Diabetes of Youth (MIDY) with insulin deficiency. To gain insights into the molecular basis of this diabetes-associated mutation, we perform molecular dynamics simulations in wild-type and mutant (CysA7 to Tyr or C(A7)Y) insulin A chain in aqueous solutions.

• AWE-WQ: Fast-Forwarding Molecular Dynamics Using the Accelerated Weighted Ensemble

  Journal of chemical information and modeling 54.10 (2014): 3033-3043.

  high energy barriers trap the system in these states. Recently the weighted ensemble (WE) family of methods have emerged which can flexibly and efficiently sample conformational space without being trapped and allow calculation of unbiased rates.

• Modeling Conformational Ensembles of Slow Functional Motions in Pin1-WW

  PLoS computational biology 6.12 (2010): e1001015.

  studies can map these dynamics. However, defining the network of inter-converting conformers that underlie the relaxation data remains generally challenging. Here, we combine NMR relaxation experiments with simulation to visualize networks of inter-converting conformers.

• ATP-driven Non-equilibrium Activation of Kinase Clients by the Molecular Chaperone Hsp90

  Biophysical Journal 119.8 (2020): 1538-1549.

  The molecular chaperone 90-kDa heat-shock protein (Hsp90) assists the late-stage folding and activation of diverse types of protein substrates (called clients), including many kinases. Previous studies have established that the Hsp90 homodimer undergoes an ATP-driven cycle through open and closed conformations. Here I propose a model of client activation by Hsp90, which predicts that this…

• Molecular Simulations Minimally Restrained by Experimental Data

  The Journal of chemical physics 150.15 (2019): 154121.

  One popular approach to incorporating experimental data into molecular simulations is to restrain the ensemble average of observables to their experimental values. Here, I derive equations for the equilibrium distributions generated by restrained ensemble simulations and the corresponding expected values of observables. My results suggest a method to restrain simulations so that they generate distributions…

• Cochaperones Enable Hsp70 to Use ATP Energy for Non-Equilibrium Sta- bilization of Native Proteins

  Biophysical Journal 116.3 (2019): 339a.

  The heat shock protein 70 (Hsp70) chaperones, vital to the proper folding of proteins inside cells, consume ATP and require cochaperones in assisting pro- tein folding. It is unclear whether Hsp70 can utilize the free energy from ATP hydrolysis to fold a protein into a native state that is thermodynamically unsta- ble in the chaperone-free…

• The Hsp70 Interdomain Linker Is a Dynamic Switch That Enables Allosteric Communication Between Two Structured Domains

  Journal of Biological Chemistry 292.36 (2017): 14765-14774.

  Hsp70 molecular chaperones play key roles in cellular protein homeostasis by binding to exposed hydrophobic regions of incompletely folded or aggregated proteins. This crucial Hsp70 function relies on allosteric communication between two well-structured domains: an N-terminal nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain (SBD), which are tethered by an interdomain linker. ATP or ADP…

HPC and Custom Hardware

• Fully Integrated FPGA Molecular Dynamics Simulations

  Proceedings of the International Conference for High Performance Computing, Networking, Storage and Analysis. 2019.

  The implementation of Molecular Dynamics (MD) on FPGAs has received substantial attention. Previous work, however, has consisted of either proof-of-concept implementations of components, usually the range-limited force; full systems, but with much of the work shared by the host CPU; or prototype demonstrations, e.g., using OpenCL, that neither implement a whole system nor have competitive…

• Molecular Dynamics Range-Limited Force Evaluation Optimized for FPGAs

  2019 IEEE 30th International Conference on ASAP. Vol. 2160. IEEE, 2019.

  FPGA Molecular Dynamics was much studied from 2004-2010. Due to limited chip resources of that era, and the inherent variety and complexity of tasks comprising Molecular Dynamics simulations (MD), those FPGA accelerators relied on host or embedded processors to organize and pre-process input and output data. This introduced long latency for data movement between simulation…