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Graham Randall
Baylor College of MedicineDepartment: SCBMB ProgramAddress: One Baylor Plaza, N215 Houston, TX 77030 Phone: Fax: Email: grandall@bcm.edu Web: grandall.org |
Education
B. A. Applied Mathematics, U. C. Berkeley (1994)
Honors
Predoctoral Fellow, The W.M. Keck Center for Computational and Structural Biology, 2004-2006
Scholarship Winner, Gulf Coast Mensa, 2006
Best SCBMB Poster, CMB/SCBMB Annual Retreat, 2005
Sponsored Attendee, Summer Computing Institute, San Diego Supercomputer Center, 2005
Professor John J. Trentin Scholarship Award, 2004
Baylor 10 Scholar, 2003
Meritorious Prize, Mathematical Contest in Modeling, 1994
Texaco Philanthropic Foundation Scholarship, 1990-1994
Service
Member, SCBMB Executive Committee, BCM, 2005-2006
Teaching Assistant, Computational Mathematics for Biomedical Scientists, BCM, Fall 2005
Volunteer, Texas Children's Hospital, 2003-2006
Great Decisions Group Leader, Houston World Affairs Council, 2005-2006
Great Decisions Group Member, Houston World Affairs Council, 2004-2005
Member, Biomedical Technology Club of Houston, 2003-2006
Member, Rice Alliance for Technology and Entrepreneurship, 2005-2006
Member, Provost�s Student Advisory Committee, UCB, 1993-1994
President, Mathematics Undergraduate Student Association, UCB, 1993-1994
Research Topic
Multi-Scale Simulations of Type-II Topoisomerases
Research Description
Type II topoisomerases untie knots, unlink catenanes, and relax DNA supercoils. These problematic topologies arise as a consequence of DNA replication and recombination. Requiring ATP and magnesium, type II topoisomerases function by breaking both strands of one DNA double-helix, passing an intact DNA helix through the breaks while remaining bound to the free ends of the cleaved helix, and then religating the strands. Failure to restore nominal DNA topology prohibits cell division and can result in cell death or cancer. Such catastrophic consequences make topoisomerases an effective target for antibiotics and anticancer agents. Despite their biological and clinical importance, little is understood about how a topoisomerase identifies topological anomalies in a molecule that is significantly larger than the topoisomerase itself.
The Zechiedrich laboratory has proposed that type II topoisomerases recognize angle and curvature between two DNA helices characteristic of knotted and catenated DNA to account for the enzyme's preference to unlink instead of link DNA. Specifically, it is proposed that these enzymes act on so-called "hooked" juxtapositions (where the helices curve towards each other) and ignore "free" juxtapositions (where the helices curve away from each other). The electrostatics of DNA-DNA interactions are poorly understood and represent one possible driver of hooked versus free juxtaposition formation. Previous data showed that a hooked juxtaposition of charged strings in vacuum tended to persist because of electrostatic interactions, thus a type II topoisomerase would be more likely to encounter the juxtaposition and act. I have been considering the effect of electrolytes on the persistence of hooked versus free juxtapositions to better understand the physics behind DNA-DNA interactions and to determine the possibility of juxtapositions occurring through Brownian diffusion.
Molecular modeling of topoisomerase is complicated by the fact that despite years of study and several attempts by many laboratory researchers, no complete crystal structure of a type II topoisomerase exists. This may be due to the size of the molecule (~350 kDa), its conformational malleability required to carry out its function, or its extreme hydrophobicity. I am also attempting to supplement my molecular models with structural data produced by three-dimensional reconstructions of human topoisomerase II-alpha using images acquired by electron cryo-microscopy.
This work is supported by a training fellowship from the Keck Center for Computational and Structural Biology of the Gulf Coast Consortia (NLM Grant No. 5T15LM07093).
Selected Publications
- GL Randall, BM Pettitt, DWL Sumners, L Zechiedrich (2008) “Waiting for Boltzmann; DNA Topology Drives Topoisomerase Activity” (in preparation)
- GL Randall, L Zechiedrich, BM Pettitt (2008) “To preserve B-form, DNA relieves torsional stress with localized, sequence-dependent base-flipping, denaturation, and formation of P-DNA.” (submitted)
- JM Fogg, DJ Catanese, GL Randall, MC Swick, L Zechiedrich (2008) “Differences between positively and negatively supercoiled DNA that topoisomerases may distinguish.” Proc. Institute Math. App. (in press)
- LS Becnel, RL Atmar, GL Randall, RJ Hamill, D Steffen, and L Zechiedrich (2008) “Increased Escherichia coli fluoroquinolone resistance in a large county hospital as a function of time, culture site and patient age, sex, and location.” BMC Infect Dis, 8:4
- GL Randall, BM Pettitt, GR Buck, EL Zechiedrich (2006) “Electrostatics of DNA-DNA juxtapositions: Consequences for type II topoisomerase function.” J. Phys. Cond. Matter, 18:S173-185 (cover article)
Last edited on: September 25, 2009