Members of our senior science team are the lead authors on publications appearing in industry journals, with over 200 peer-reviewed articles and over 20,000 citations. Insights and expertise of our scientists enable us to address difficult protein targets through a fundamental understanding of disease at the atomic level. We believe our thought leadership—coupled with our integrated in-house experimental efforts in chemistry and biology and our high-performance computing environment—will lead to design and delivery of new safe and effective medicines to improve the lives of patients.
Binding Free Energies
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).…
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…
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.
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.
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.
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…
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…
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
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…
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…