People Detail

Faculty Biography For:

James Briggs
Associate Professor
Ph.D., Department of Chemistry, Purdue University, 1990

Biology and Biochemistry Department
University of Houston
Houston, Texas 77204-5001

Office: HSC 402D
Phone: 713-743-8366

Computer-Aided Molecular Design; Molecular Simulations; Protein Structure and Function; Inhibitor Design
Our research is focused on computational studies of protein structure and function, inhibitor design, investigations of possible inhibitor resistance pathways, and development of methods for the above project areas. Targets for these studies include those important in the treatment of AIDS, cancer, bacterial infections, and other disease states. In addition, we work on inhibitors to aid in biowarfare defense (botulinum neurotoxins, anthrax toxin, cholera toxin).

Activities currently underway in my group involve the use and development of computer programs on high-performance computers to study the kinetic and thermodynamic properties of enzymes and receptors. Application areas include the search for inhibitors of the HIV-1 integrase, structural and mechanistic studies of various bacterial enzymes, and more. Docking from 3D structural databases, molecular mechanics, molecular and Brownian dynamics, electrostatics, quantum mechanics, QSAR, and other methods are used in the work mentioned above.

Antiviral drug design
The HIV-1 integrase splices the proviral genome into the host DNA thereby tricking the host cell machinery into making viral proteins. This enzyme, for which no good inhibitors are known, represents the third of the main enzyme targets in HIV. Work on this project is performed in collaboration among five research groups (X-ray crystallography, virology, computational biochemistry, organic synthesis, and marine biology) that represent a complete structure-based inhibitor design cycle/team. Our early results on this project are providing some clues about the structure of the active site. The initial small molecule docking studies have revealed hot spots for new functional group types that we are incorporating into newly designed lead compounds. A dynamic pharmacophore method has been developed that takes protein flexibility into account, which appears very promising.

Antibacterial drug design; Biophysical studies
Studies are also underway on the dynamics and inhibition of bacterial alanine racemases. These enzymes are found only in bacteria and are required for the first step in enzymatic synthesis of the peptidoglycan layer. These enzymes represent targets for broad spectrum anti-bacterial drug design efforts. This project represents a collaboration between our group (computational biochemistry) and X-ray crystallography, molecular biology, and organic chemistry research groups. We start with three-dimensional structures of alanine racemases, carry out molecular dynamics simulations, docking calculations, and finally database searching in order to under the function and inhibition of these enzymes, and to identify novel potential new drug candidates.

In addition to the drug design projects, we have interests in the re-engineering of enzyme substrate specificity, and in a number of basic science areas centering on electrostatic properties of biomolecules. We have a collaboration with a biochemistry group in this department to assist in the rational redesign of the substrate binding pocket for the leucyl tRNA synthetase. In this way, non-natural amino acids might then be more easily incorporated into proteins during protein biosynthesis. We are also interested in developing a method, based on electrostatic properties, for rapidly and reliably predicting locations of specific metal ion binding sites in RNA molecules. The knowledge of such sites is essential to understanding the structures and catalytic mechanisms of RNA molecules. Another example where electrostatic is important in understanding structure and function is for the phosphate binding protein. This protein has a negative electrostatic substrate binding pocket, although the substrate is dianionic (HPO42-) at pH 7. The substrate should be repelled by its binding pocket, so what is the mechanism of attraction of the substrate by the protein? We have revealed the answer to this question by carrying out Brownian dynamics simulations.

Most of the activities in my group are focused on enzymes that are targets for inhibitor design. Greater understanding of the reaction mechanisms, structural dynamics, and of the effects of point mutations should lead to more rational design of next generation inhibitors for these enzymes, that may be less prone to acquired resistance. My group members carry out their calculations on supercomputers, UNIX workstations, and on our Beowulf cluster. I teach courses, at the undergraduate and graduate levels, on the application of molecular modeling techniques to problems of biochemical interest.

Huang HC, Jupiter D, Qiu M, Briggs JM, Vanburen V. (2008). Cluster analysis of hydration waters around the active sites of bacterial alanine racemase using a 2-ns MD simulation. Biopolymers, 89(3):210-9.

Biopolymers, 2008, 89, 1104-1113

Zhai Y, Nawaz MH, Lee KW, Kirkbride E, Briggs JM, Martinis SA. (2007). Modulation of substrate specificity within the amino acid editing site of leucyl-tRNA synthetase. Biochemistry, 46(11):3331-7.

Deng J, Sanchez T, Neamati N, Briggs JM. (2006). Dynamic pharmacophore model optimization: identification of novel HIV-1 integrase inhibitors. Journal of Medicinal Chemistry, 49(5):1684-92.

Mustata, G. I.; Brigo, A.; Briggs, J. M. "HIV-1 Integrase Pharmacophore Model Derived from Diverse Classes of Inhibitors", Bioorg. Med. Chem. Lett., 2004, 14, 1447-1454.

Lee MC, Deng J, Briggs JM, Duan Y. (2005). Large-scale conformational dynamics of the HIV-1 integrase core domain and its catalytic loop mutants. Biophysical Journal, 88(5):3133-46.

Brigo A, Mustata GI, Briggs JM, Moro S. (2005). Discovery of HIV-1 integrase inhibitors through a novel combination of ligand and structure-based drug design. Medicinal Chemistry, 1(3):263-75.

Brigo A, Lee KW, Fogolari F, Mustata GI, Briggs JM. (2005). Comparative molecular dynamics simulations of HIV-1 integrase and the T66I/M154I mutant: binding modes and drug resistance to a diketo acid inhibitor. Proteins, 59(4):723-41.

Brigo A, Lee KW, Iurcu Mustata G, Briggs JM. (2005). Comparison of multiple molecular dynamics trajectories calculated for the drug-resistant HIV-1 integrase T66I/M154I catalytic domain. Biophysical Journal, 88(5):3072-82.

LeMagueres P, Im H, Ebalunode J, Strych U, Benedik MJ, Briggs JM, Kohn H, Krause KL. (2005) The 1.9 A crystal structure of alanine racemase from Mycobacterium tuberculosis contains a conserved entryway into the active site. Biochemistry, 44(5):1471-81.

Mulder BA, Anaya S, Yu P, Lee KW, Nguyen A, Murphy J, Willson R, Briggs JM, Gao X, Hardin SH. (2005). Nucleotide modification at the gamma-phosphate leads to the improved fidelity of HIV-1 reverse transcriptase. Nucleic Acids Research, 33(15):4865-73.

Mursinna, R. S.; Lee, K. W.; Briggs, J. M.; Martinis, S. A. Molecular Dissection of a Critical Specificity Determinant within the Amino Acid Editing Domain of Leucyl-tRNA Synthetase, Biochem., 2004, 43, 155-165.

Barreca ML, Rao A, De Luca L, ZappalĂ  M, Gurnari C, Monforte P, De Clercq E, Van Maele B, Debyser Z, Witvrouw M, Briggs JM, Chimirri A. (2004). Efficient 3D database screening for novel HIV-1 IN inhibitors. Journal Of Chemical Information And Computer Science, 44(4):1450-5.

Mustata G, Briggs JM. (2004). Cluster analysis of water molecules in alanine racemase and their putative structural role. Protein Engineering, Design & Selection, 17(3):223-34.

Lee KW, Briggs JM. (2004). Molecular modeling study of the editing active site of Escherichia coli leucyl-tRNA synthetase: two amino acid binding sites in the editing domain. Proteins, 54(4):693-704.

Mustata, G. I.; Briggs, J. M. Molecular Dynamics Studies of Alanine Racemase: A Structural Model for Drug Design, Biopolymers, 2003, 70, 186-200.

Barreca, M. L.; Chimirri, A.; Briggs, J. M. Molecular dynamics studies of the wild-type and double mutant HIV-1 integrase complexed with the 5CITEP inhibitor: mechanism for inhibition and drug resistance, Biophys. J., 2003, 84, 1450-1463.

Mustata, G. I.; Briggs, J. M. A Structure-Based Design Approach for the Identification of Novel Inhibitors: Application to an Alanine Racemase, J. Comput.-Aided Mol. Design, 2002, 16, 935-953.

Soares, T. A.; Lins, R. D.; Straatsma, T. P.; Briggs, J. M. Internal Dynamics and Ionization States of the Macrophage Migration Inhibitory Factor: Comparison Between the Wild-Type and Mutant Forms, Biopolymers, 2002, 65, 313-23.

Huang H.-C.; Briggs, J. M. The Association Between a Negatively Charged Ligand and the Electronegative Binding Pocket of its Receptor, Biopolymers, 2002, 63, 247-260.

Ondrechen, M. J.; Briggs, J. M.; McCammon, J. A. "A Model for Enzyme-Substrate Interaction in Alanine Racemase", J. Am. Chem. Soc., 2001, 123, 2830-2834.

Lee, K. W.; Briggs, J. M. "Comparative Molecular Field Analysis (CoMFA) Study of Epothilones as Tubulin Inhibitors: Pharmacophore Search Using 3D QSAR Methods", J. Computer-Aided Mol. Design, 2001, 15, 41-55.

Liu, N.; Samartzidou, H.; Lee, K. W.; Briggs, J. M.; Delcour, A. H. "Effects of Pore Mutations and Permeant Ion Concentration on the Spontaneous Gating Activity of OmpC Porin", Protein Eng., 2000, 13, 491-500.

Lins, R. D.; Straatsma, T. P.; Briggs, J. M. "Similarities in the HIV-1 and ASV Integrase Active Site upon Metal Binding", Biopolymers, 2000, 53, 308-15.

Soares, T.; Briggs, J. M.; Goodsell, D.; Olson, A. "Ionization State and Molecular Docking Studies for the Macrophage Migration Inhibitor Factor: The Role of Lysine 32 in the Catalytic Mechanism", J. Mol. Recog., 2000, 13, 146-156.

Carlson, H. A.; Masukawa, K. M.; Rubens, K.; Bushman, F. D.; Jorgensen, W. L.; Lins, R. D.; Briggs, J. M.; McCammon, J. A. "Developing a Dynamic Pharmacophore Model for HIV-1 Integrase", J. Med. Chem., 2000, 43, 2100-2114.

Lins, R. D.; Adesokan, A.; Soares, T. A.; Briggs, J. M. "Investigations on Human Immunodeficiency Virus Type-1 Integrase/DNA Binding Interactions via Molecular Dynamics and Electrostatics Calculations", Pharm. Therap., 2000, 85, 123-131.

Carlson, H. A.; Briggs, J. M.; McCammon, J. A. "Calculation of the Titration Curves of the Ligands and Side Chains of E. Coli D-ala:D-ala Ligase", J. Med. Chem., 1999, 42, 109-117.

Soares, T. A.; Goodsell, D. S.; Briggs, J. M.; Ferreira, R.; Olson, A. J. "Docking of 4-Oxalocrotonate Tautomerase Substrates: Implications for the Catalytic Mechanism", Biopolymers, 1999, 50, 319-328.

Scheeff, E. D.; Briggs, J. M.; Howell, S. B. "Molecular Modeling of the Intrastrand Guanine-Guanine Adducts produced by Cisplatin and Oxaliplatin", Mol. Pharm., 1999, 56, 633-643.

Lins, R. D.; Briggs, J. M.; Straatsma, T. P.; Carlson, H. A.; Greenwald, J.; Choe, S.; McCammon, J. A. "Molecular Dynamics Studies of the HIV-1 Integrase Catalytic Domain", Biophys. J., 1999, 76, 2999-3011.

Briggs, J. M.; Antosiewicz, J. "Simulation of pH-dependent Properties of Proteins Using Mesoscopic Models", In "Reviews in Computational Chemistry", K. N. Lipkowitz and D. B. Boyd, Eds., 1999, Vol. 13, Ch. 5, 249-311.

Carlson HA, Briggs JM, McCammon JA. (1999). Calculation of the pKa values for the ligands and side chains of Escherichia coli D-alanine:D-alanine ligase. Journal Of Medicinal Chemistr, 42(1):109-17.

Scheeff ED, Briggs JM, Howell SB. (1999). Molecular modeling of the intrastrand guanine-guanine DNA adducts produced by cisplatin and oxaliplatin. Molecular Pharmacology, 56(3):633-43.

Weber W, Demirdjian H, Lins RD, Briggs JM, Ferreira R, McCammon JA. (1998). Brownian and essential dynamics studies of the HIV-1 integrase catalytic domain. Journal Of Biomolecular Structure And Dynamics, 16(3):733-45.

Baginski M, Fogolari F, Briggs JM. (1997). Electrostatic and non-electrostatic contributions to the binding free energies of anthracycline antibiotics to DNA. Journal of Molecular Biology, 274(2):253-67.

Fogolari F, Elcock AH, Esposito G, Viglino P, Briggs JM, McCammon JA. (1997). Electrostatic effects in homeodomain-DNA interactions. Journal of Molecular Biology, 267(2):368-81.

Marrone TJ, Straatsma TP, Briggs JM, Wilson DK, Quiocho FA, McCammon JA. (1996). Theoretical study of inhibition of adenosine deaminase by (8R)-coformycin and (8R)-deoxycoformycin. Journal Of Medicinal Chemistry, 39(1):277-84.

Antosiewicz J, Briggs JM, McCammon JA. (1996). Orientational steering in enzyme-substrate association: ionic strength dependence of hydrodynamic torque effects. European Biophysics Journal, 24(3):137-41.

Wlodek ST, Antosiewicz J, McCammon JA, Straatsma TP, Gilson MK, Briggs JM, Humblet C, Sussman JL.(1996). Binding of tacrine and 6-chlorotacrine by acetylcholinesterase. Biopolymers, 38(1):109-17.

Cannon WR, Briggs JM, Shen J, McCammon JA, Quiocho FA. (1995). Conservative and nonconservative mutations in proteins: anomalous mutations in a transport receptor analyzed by free energy and quantum chemical calculations. Protein Science: A Publication Of The Protein Society, 4(3):387-93.

Wade RC, Luty BA, Demchuk E, Madura JD, Davis ME, Briggs JM, McCammon JA. (1994). Simulation of enzyme-substrate encounter with gated active sites. Nature Structural Biology, 1(1):65-9.