Tom Cheatham
Assistant Professor of Medicinal Chemistry and of Pharmaceutics and Pharmaceutical Chemistry
B.A. Middlebury College
Ph.D. University of California, San Francisco
Research
Our research involves the development of molecular dynamics and free energy simulation methodologies (AMBER and CHARMM) and their application to proteins, nucleic acids and lipids in their native environments. Thanks to advances in computer power, empirical force fields for bio-molecular systems, and methodological enhancements, we have witnessed tremendous advance in our ability to reliably represent the structure, dynamics, energetics and interactions of a wide variety of systems. Despite these advances, there are still major issues related to the energetic representation and the sampling of thermally accessible conformations. Through the application of these methods to bio-molecular systems we not only expose these deficiencies and investigate means to overcome them, but provide insight above and beyond what can be seen experimentally. Specific areas of recent interest include: (a) the environmental dependence of nucleic acid and protein structure, (b) investigation of the pathways of complex conformational transitions and (c) the role of flexibility and dynamics in structure and function.
Average hydration (blue), ethanol oxygen (red) and Na+ ion association (yellow) around an average DNA structure from a two nanosecond MD simulation.
Environmental Dependence of Nucleic Acids The structure and dynamics of nucleic acids are profoundly influenced by their environment: small changes in the salt concentration or identity, hydration or protein binding can radically alter the properties of DNA. Recently, we have shown that molecular dynamics simulations can reproduce these structure alterations, giving detailed insight into the process. Currently, work is underway to investigate the specific role of ion binding on DNA bending.
Forcing conformational transitions The rough and complex energy surface of biological macromolecules, coupled with computational limits that restrict accurate simulation to the 1-50 ns time range, inhibit the spontaneous observation of large and functionally important structural changes. To enhance sampling, we are developing and applying methods that allow unbiased searching of complex conformational transitions, such as propagation of a B-DNA/Z-DNA junction and the structural changes induced by prolyl isomerases.
Flexibility in structure and function? Contrary to the static picture of bio-molecules seen from the millisecond time averaged structures from crystallography or NMR, bio-molecular structures are extremely dynamic. MD simulations coupled with other methods, over various time scales, can give detailed insight into role of macomolecular dynamics and ultimately how to modulate them to alter function.
References
1. Cheatham III TE (2004) Simulation and modeling of nucleic acid structure, dynamics and interactions. Curr. Opin. Struct. Biol. 14:360-367
2. Beveridge DL, Barreiro G, Byun KS, Case DA, Cheatham III TE, Dixit SB, Giudice E, Lankas F, Lavery R, Maddocks J, Osman R, Sklenar H, Stoll G, Thayer KM, Varnai P, Young MA (2004) Molecular dynamics simulations of the 136 unique tetranucleotide sequences of DNA oligonucleotides. I. Research design, informatics, and results on d(CpG) steps. Biophys. J. 87:3799-3813
3. Lankas F, Sponer J, Langowski J, Cheatham III TE (2004) DNA deformability at the base pair level. J. Amer. Chem. Soc. 126:4124-4125
4. Fadrna E, Spackova N, Stefl R, Koca J, Cheatham III TE, Sponer J (2004) Molecular dynamics simulations of guanine quadruplex loops: Advances and force field limitations. Biophys. J. 87:227-242
5. Lankas F, Sponer J, Langowski J, Cheatham III TE (2003) DNA base-pair step deformability inferred from molecular dynamics simulation. Biophys. J. 85:2872-2883
6. Lewis JP, Cheatham III TE, Wang H, Starikow E, Sankey OF (2003) Dynamically amorphous character of electronic states in poly(dA)-poly(dT) DNA. J. Phys. Chem. B 107:2581-2587
7. Stefl R, Cheatham III TE, Spackova N, Fadrna E, Berger I, Koca J, Sponer J (2003) Folding pathways of a guanine-quadruplex DNA revealed by molecular dynamics and thermodynamical analysis of the substates. Biophys. J. 85:1787-1804
8. Spackova N, Cheatham III TE, Ryjacek F, Lankas F, van Meervelt L, Hobza P, Sponer J (2003) Molecular dynamics simulations and thermodynamics analysis of DNA-drug complexes. Minor groove binding between 4'-6-diamino-2-phenylindole and DNA duplexes in solution. J. Amer. Chem. Soc. 125:1759-1769
