American Chemical Society Division of Computers in Chemistry ABSTRACTS 226th ACS National Meeting New York, NY September 07-11, 2003 R. A. Wheeler, W. D. Cornell, Program Chairs SUNDAY MORNING • Frontiers in DNA Research: An Interdisciplinary Symposium J. D. Evanseck, Organizer Papers 1-4 • Parallel and High-Performance Computing in Chemistry D. E. Bernholdt, Organizer, Presiding Papers 5-8 • Theory and Simulation of Protein Folding Kinetics J. Pitera, Organizer Papers 9-14 SUNDAY AFTERNOON • Frontiers in DNA Research: An Interdisciplinary Symposium J. D. Evanseck, Organizer Papers 15-19 • Parallel and High-Performance Computing in Chemistry D. E. Bernholdt, Organizer; T. L. Windus, Presiding Papers 20-23 • Theory and Simulation of Protein Folding Kinetics J. Pitera, Organizer Papers 24-29 • Challenges for the Chemical Sciences in the 21st Century: Information and Communication P. Gund, Organizer, Presiding Papers 30-35 MONDAY MORNING • Frontiers in DNA Research: An Interdisciplinary Symposium J. D. Evanseck, Organizer Papers 36-39 • Parallel and High-Performance Computing in Chemistry D. E. Bernholdt, Organizer; R. J. H. Harrison, Presiding Papers 40-42 • Modeling Spin Forbidden and Open-Shell Processes T. Cundari, Organizer Papers 43-46 • Computational Chemistry in Drug Discovery: Are High Information Content Calculations Better than Low Information Content Calculations J. L. Miller, Organizer Papers 47-54 MONDAY AFTERNOON • Frontiers in DNA Research: An Interdisciplinary Symposium J. D. Evanseck, Organizer Papers 55-59 • Computational Chemistry in Drug Discovery: Are High Information Content Calculations Better than Low Information Content Calculations J. L. Miller, Organizer Papers 60-67 • Modeling Spin Forbidden and Open-Shell Processes T. Cundari, Organizer Papers 68-71 MONDAY EVENING • Sci-Mix R. A. Wheeler, Organizer Papers 106, 111, 114, 120-121, 126, 132-134, 137-138, 142-144, 146-148, 153, 155, 159, 162-163, 170, 172, 175-176 TUESDAY MORNING • Frontiers in DNA Research: An Interdisciplinary Symposium J. D. Evanseck, Organizer Papers 72-75 • Structure Based Drug Design in Signal Transduction and Cell Cycle E. Lunney, Organizer Papers 76-81 • Modeling Spin Forbidden and Open-Shell Processes T. Cundari, Organizer Papers 82-86 TUESDAY AFTERNOON • Frontiers in DNA Research: An Interdisciplinary Symposium J. D. Evanseck, Organizer Papers 87-91 • Structure Based Drug Design in Signal Transduction and Cell Cycle E. Lunney, Organizer Papers 92-97 • Emerging Technologies in Computational Chemistry C. M. Breneman, Organizer Papers 98-104 TUESDAY EVENING • Computers in Chemistry Posters R. A. Wheeler, Organizer Papers 105-176 WEDNESDAY MORNING • The Challenge of Simulating Fluid Properties for Industry R. D. Mountain, Organizer Papers 177-180 • Structure Based Drug Design in Signal Transduction and Cell Cycle E. Lunney, Organizer Papers 181-186 • Computational and In Vitro ADME data: What is it Worth and How to Use It? P. D. J. Grootenhuis, Presiding Papers 187-195 WEDNESDAY AFTERNOON • The Challenge of Simulating Fluid Properties for Industry R. D. Mountain, Organizer Papers 196-199 • Structure Based Drug Design in Signal Transduction and Cell Cycle E. Lunney, Organizer Papers 200-205 • General Contributions R. A. Wheeler, Organizer Papers 206-214 THURSDAY MORNING • The Challenge of Simulating Fluid Properties for Industry R. D. Mountain, Organizer Papers 215-219 • Structure Based Drug Design in Signal Transduction and Cell Cycle E. Lunney, Organizer Papers 220-225 • General Contributions R. A. Wheeler, Organizer Papers 226-235 THURSDAY AFTERNOON • Structure Based Drug Design in Signal Transduction and Cell Cycle E. Lunney, Organizer Papers 236-241 • General Contributions R. A. Wheeler, Organizer; J. D. Madura, Presiding Papers 242-248 • General Contributions R. A. Wheeler, Organizer Papers 249-257 DIVISION OF COMPUTERS IN CHEMISTRY 1. advantage of providing for numerous contacts in both DNA grooves on a G-QUADRUPLEXES: THEIR IMPORTANCE IN GENE SILENCING, AS TARGETS relatively low molecular weight scaffold that covers long DNA sequences. FOR DRUG DESIGN, AND IN THE ETIOLOGY OF COLORECTAL CANCER. Laurence H. Hurley, College of Pharmacy, University of Arizona, 1703 E. Mabel, PO Box 210207, Tucson, AZ 85721, Fax: 520-626-5623, [email protected] The role of secondary DNA structures in control of gene expression has long 4. been debated. In this presentation I provide direct evidence for a G-quadruplex CONTROLLING NUCLEIC ACID STRUCTURAL TRANSITIONS BY in a promoter region and its targeting with a small molecule to repress c-MYC INTERCALATION. Nicholas V. Hud, and Swapan Jain, School of Chemistry and transcription. The nuclease hypersensitivity element III1 upstream of the P1 Biochemistry, Georgia Institute of Technology, 770 State St., Atlanta, GA 30332, promoter of c-MYC controls up to about 85%of the transcriptional activation of Fax: 404-894-2295, [email protected] this gene. We have demonstrated that the purine-rich strand of the DNA in this We are investigating the utility for small molecule intercalation to drive nucleic region can form two different intramolecular G-quadruplex structures, only one acid structural transitions. We have recently shown that coralyne, a small of which appears to be biologically relevant. This biologically relevant structure crescent-shaped molecule, can cause complete and irreversible duplex dispro- is the kinetically favored chair-form G-quadruplex, which when mutated with a portionation (Polak & Hud, 2002, Nucleic Acids Res. 30, p983). That is, upon single G to A transition is destabilized, resulting in a 3-fold increase in basal addition of coralyne the strands of duplex poly(dT)иpoly(dA) repartition into transcriptional activity of the c-MYC promoter. The cationic porphyrin TMPyP4, equal molar equivalents of triplex poly(dT)иpoly(dA)иpoly(dT) and single which has been shown to stabilize this G-quadruplex structure, is able to further stranded poly(dA). We have also discovered that poly(dA) forms a duplex suppress c-MYC transcriptional activation. These results provide compelling self-structure in the presence of coralyne, which is completely dependanton evidence that a specific G-quadruplex structure formed in the c-MYC promoter coralyne intercalation for stability. Similar investigations have now been carried region functions as a transcriptional repressor element. Furthermore, we out with homo-dT and homo-dA oligonucleotides of 16 and 32 nucleotides in establish the principle that c-MYC transcription can be controlled by ligand- length. We will show that duplex disproportionation by coralyne is profoundly mediated G-quadruplex stabilization. The formation of similar G-quadruplexes in dependant on oligonucleotide length. For example, disproportionation is other promoters of growth regulatory genes, such as PDGF-A, c-myb, and reversible with temperature for dT иdA over the course of hours, but requires Ki-ras, suggest that this will be a more general phenomenon in genes associ- 16 16 days for dT иdA , and is apparently irreversible for poly(dT)иpoly(dA). An ated with growth and proliferation. Furthermore, we have identified the same G 16 32 equilibrium state containing three different secondary structures (i.e. duplex, to A mutation in the c-MYC repressor element, which results in inactivationof triplex and the AиA duplex) can also be achieved at certain temperatures, the G-quadruplex repressor element and overexpression of c-MYC in 30%of depending upon oligonucleotide length. The interplay we observe between patients with colorectal cancer. coralyne intercalation, temperature and nucleic acid secondary structure reveals a system of intertwined thermodynamic and kinetic factors. 2. PROGRAMMED READ-OUT OF THE DNA MINOR GROOVE BY SYNTHETIC LIGANDS. Peter B. Dervan, Department of Chemistry, California Institute of Technology, Mail Code 164-30, Pasadena, CA 91125, [email protected] Small molecules that specifically bind predetermined DNA sequences wouldbe 5. useful tools in biology, biotechnology and potentially in human medicine. PARALLELIZATION OF THE EFFECTIVE FRAGMENT METHOD FOR SOLVATION Synthetic ligands are designed to read the DNA double helix in the minor groove AND EXTENSIONS TO MODEL BULK BEHAVIOR. Heather Netzloff, and M. S. by a set of simple chemical principles. Hairpin pyrrole-imidazole polyamides Gordon, Department of Chemistry, Iowa State University, 201 Spedding Hall, achieve affinities and specificities comparable to DNA-binding proteins. The Ames, IA 50011, [email protected] design of second generation ring pairing rules for distinguishing the four Watson-Crick base pairs will be described. As the size of a system grows, ab initio quantum chemistry calculations quickly increase in computational cost. In order to accurately model liquids and solvation effects, a large number of molecules is required. The Effective 3. Fragment Potential (EFP) method for solvation has been developed, in part,to THREADING POLYINTERCALATION. Brent L. Iverson, Jeeyeon Lee, and Vladimir address these concerns. In the method, the system is divided into an ab initio Guelev, Department of Chemistry & Biochemistry, The University of Texas at region that contains the solute plus some number of solvent molecules, if Austin, 1 University Station, Austin, TX 78712, Fax: 512-471-8696, desired, and an “effective fragment” region that contains the remaining solvent [email protected] molecules. Interaction between solvent molecules, represented by effective Threading intercalators