Thomas E. Cheatham, PhD

The people in our lab use and develop molecular dynamics, free energy simulation, and trajectory analysis methodologies in applications aimed at better understanding biomolecular structure, dynamics and interactions. A strong focus of our funded efforts centers on the reliable representation of nucleic acid systems (DNA and RNA) in solution. For example, we helped solved the NMR structure of the drug-bound Hepatitis C virus IRES structure shown on the left. Based on this (and related structures), we can now apply CADD methods and simulation to better understand and design potential new Hepatitis C therapeutics. In addition, large efforts are underway to better characterize RNA structure and force fields through simulation of a large number of commonly observed RNA structural motifs and a large variety of NMR and crystal structures. We are also involved with international collaborative efforts to understand DNA structure, for example through the ABC consortium and long simulations of DNA...

Critical to reliable representation of the structure, dynamics and interactions is not only trying to simulation the biomolecules in their native solution environment but to also both critically assess and validate the simulation results with experiment. Our group focuses on both brute-force and enhanced sampling/ensemble-based simulation using available high performance computational resources at the University of Utah (www.chpc.utah.edu) and elsewhere. Outside resources include large allocations of computer time from Blue Waters, XSEDE (www.xsede.org), on the Anton machine at PSC and from other sources. With these resources we also are able to expose and overcome limitations in the methods and force fields...

Beyond nucleic acids, we are also interested in various coiled-coils, enzymes and cytochrome P450's. A key emphasis is on improving stability or understanding how ligands alter receptor structure upon binding. Also, in addition to continued development of the ptraj/cpptraj tools within the AmberTools suite for analysis of MD trajectories, we are exploring methods to mine more information from the simulation data and means to more broadly disseminate the MD results.

Although our primary development and simulation engine is AMBER, we also use and have experience with CHARMM, NAMD, and other programs.

GRANTS

Research in the lab is currently funded by various research grants, including:

1. NIH RO1-GM081411: "Biomolecular simulation for the end-stage refinement of nucleic acid structure".

(2/01/08-1/31/14) PI: Cheatham.
This core R-01 funding supports research into the development of better force fields for simulation of RNA, attempts various means to assess and validate the performance of MD simulation as applied to RNA, and seeks to explore means to more broadly disseminate MD simulation data. Here is the NIH reporter link. Currently this is in no-cost-extension.

2. NIH RO1-GM098102: "RNA-ligand interactions: Simulation and experiment".

(9/30/11-8/31/15) M-PIs: Kathleen Hall (WUSTL), Cheatham and Carlos Simmerling (Stony Brook U).
This core R-01 funding supports research into the development of better force fields for simulation of RNA, attempts various means to assess and validate the performance of MD simulation as applied to RNA, and seeks to explore means to more broadly disseminate MD simulation data. Here is the NIH reporter link

3. NSF CHE-1266307: "CDS&E: Tools to facilitate deeper data analysis, exploration, management, and sharing of ensembles of molecular dynamics trajectory data".
(10/01/13-9/30/15) PI: Cheatham
Further development of the iBIOMES environment for sharing and disseminating MD simulation data and also tools for deeper analysis (CPPTRAJ).

4. NSF ACI-1341034: "CC-NIE Integration: Science slices converting network research innovation into enhanced capability for computational science and engineering at the University of Utah".
(10/01/13-9/30/15) PI: Corbato, Co-PIs: Bolton, van der Merwe, Ricci, Cheatham
Deployment of a science DMZ network at the U of Utah.

5. NSF OCI-1035208: "PRAC - Hierarchical molecular dynamics sampling for assessing pathways and free energies of RNA catalysis, ligand binding, and conformational change".
(2/01/11-1/31/14) PI: Cheatham, Co-PIs: Simmerling (Stony Brook), Roitberg (U Florida), and York (Rutgers).
This is a travel grant that provides training and preparation for eventual usage of the "Blue Waters" supercomputer at NCSA. We are one of ~36 groups that will be given access. Here is the link to the NSF awards database.

6. NIH R01-GM074249: "P450-mediated dehydrogenation mechanisms."
(1/01/11-12/31/15) PI: Gs Yost    Co-PIs: Cheatham, Reilly
Experiment, simulation and docking probe the interaction of substrates with P450 with a focus on dehydrogenation reactions. Here is the NIH reporter link

7. NSF Cyberinfrastructure partnership, LRAC MCA01S027 (yearly)
"Insight into biomolecular structure, dynamics, interactions and energetics from simulation".
PI: Cheatham.
This is a large allocation of resources on the NSF supercomputer centers to support research in the Cheatham lab.

Recently ended grants
1. NIH R01-GM079383: "AMBER force field consortium: A coherent biomolecular simulation platform."
(9/28/07-8/31/12) PI: Y. Duan (UC Davis) Co-PIs: Cheatham, C. Simmerling (Stony Brook U), R. Luo (UC Irvine), P. Cieplak (Burnham Inst), and J. Wang.
The consortium aims to improve the AMBER force fields; our role focuses on polarizable force fields for nucleic acids. Here is the NIH reporter link.

2. Pittsburgh Supercomputing Center, PSCA00033P
"Molecular dynamics of DNA and protein-DNA complexes: A proposal for obtaining microsecond trajectories using Anton".
PI: Cheatham.

3. Pittsburgh Supercomputing Center, PSCA00067P
"Development and testing of improved fixed-charge force fields for proteins".
PI: Case.

LAB INFORMATION

OPPORTUNITIES

For research opportunities or other questions, contact Dr. Cheatham
Department of Medicinal Chemistry College of Pharmacy

• (801) 587-9652 Skaggs office
• (801) 585-6318 INSCC office
• (801) 581-3285 Lab / Group
• (801) 585-6208 (Fax)

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