Research projects

The main theme of the research is the application of modern theoretical methods and computers to solve problems concerning structure and reactivity for organic and biomolecular systems. Several specific areas of research can be noted:

QM/MM simulation of organic reactions in condensed phase

3D PMF plot Organic reactions are studied in the gas phase and solution in order to elucidate reaction mechanisms and the origins of solvent effects on reaction rates. Mixed quantum and molecular mechanics (QM/MM) combined with Monte Carlo simulations and free-energy perturbation calculations were performed in solution to obtain free-energy curves and surfaces for several processes including SN2, aromatic substitution, Diels-Alder, and Claisen reactions. More recently, this technique was extended to investigate the origin of the catalysis provided by Chorismate Mutase for the rearrangement of chorismate to prephenate and the reaction mechanism for the second step of the transformation catalyzed by Macrophomate Synthase.

  • Macrophomate Synthase: QM/MM Simulations Address the Diels-Alder versus Michael-Aldol Reaction Mechanism. Guimaraes, C. R. W ; Udier-Blagovic, M.; Jorgensen, W. L., J. Am. Chem. Soc. 127, 3577-3588 (2005). doi:10.1021/ja043905b
  • Contributions of Conformational Compression and Preferential Transition State Stabilization to the Rate Enhancement by Chorismate Mutase. C.R.W. Guimaraes, M.P. Repasky, J. Chandrasekhar, J. Tirado-Rives, W.L. Jorgensen, J. Am. Chem. Soc., 125, 6892-6899 (2003). doi:10.1021/ja021424r
  • Steric Retardation of SN2 Reactions in the Gas Phase and Solution. Vayner, G.; Houk, K.N.; Jorgensen, W.L.; Brauman, J.I., J. Am. Chem. Soc. 126, 9054-9058 (2004). doi:10.1021/ja049070m
  • Solvent Effects and Mechanism for a Nucleophilic Aromatic Substitution from QM/MM Simulations. O. Acevedo, W. L. Jorgensen, Org. Lett. 6, 2881-2884, (2004). doi:10.1021/ol049121k

Protein-ligand binding

HIV-RT Developing procedures for the efficient and accurate calculation of protein-ligand binding affinities is another focus of the lab. A three-pronged approach is utilized to evaluate protein-ligand binding. The simplest and quickest technique is a QSAR approach. Next, linear response via Monte Carlo simulations is used to determine scoring functions. The last and most rigorous approach employed is Free Energy Perturbations (FEP) to understand structural and energetic relationships to binding. Current work has addressed the binding of drug candidates to HIV reverse transcriptase, COX-2, kinase, and FK506 binding protein.

  • Validation of a Model for the Complex of HIV-1 Reverse Transcriptase with the Novel Non-nucleoside Inhibitor TMC125. M. Udier-Blagovic, J. Tirado-Rives and W. L. Jorgensen, J. Am. Chem. Soc., 125, 6016-6017 (2003). doi:10.1021/ja034308c
  • Model for Estimation of the Inhibition of Protein Kinases using Monte Carlo Simulations. Tominaga, Y. & Jorgensen, W.L. J. Med. Chem. 47, 2534-2549(2004). doi:10.1021/jm0304358

De Novo Structure-Based Drug Design

Structure-Based Drug Design cycle The design of novel HIV non-nucleoside reverse transcriptase inhibitors (NNTRIs) is pursued via a combination of synthetic and computational methods. Automated lead generation is handled with the growing program BOMB, lead optimization is studied via Monte Carlo simulations with free energy perturbation theory from MCPRO, and property analysis of possible novel inhibitors are predicted with QikProp. Once a novel inhibitor is identified through the three-levels of computation, it is then synthesized and assayed. Through key collaborations with synthetic chemists and biologists, inhibition activity is known within weeks.

Semiempirical Molecular Orbital Methods

PDDG function Significant effort is being invested in the development of improved semiempirical for use in QM/MM simulations. The PDDG/PM3 method was created from small modifications to the core-repulsion function of the PM3 method, followed by reparameterization, and resulted in a method 25% more accurate than PM3 for a test set of 1480 molecules.

Ongoing projects comprise the explicit inclusion of the overlap matrix into the Roothan-Hall equation, together with further modifications to the core repulsion function and extended parameterization with the aim of improving conformational energetics.

  • NO-MNDO: Reintroduction of the Overlap Matrix into MNDO Sattelmeyer, K. W.; Tubert-Brohman, I.; Jorgensen, W. L. J. Chem. Theory Comput. 2, 413 - 419 (2006). doi:10.1021/ct050174c
  • Extension of the PDDG/PM3 Semiempirical Molecular Orbital Method to Sulfur, Silicon, and Phosphorus. Tubert-Brohman, I.; Guimarães, C. R. W.; Jorgensen, W. L. J. Chem. Theory Comput. 1, 817-823 (2005). doi:10.1021/ct0500287
  • PDDG/PM3 and PDDG/MNDO: Improved Semiempirical Methods. M.P. Repasky, J. Chandrasekhar, and W.L. Jorgensen J. Comput. Chem., 23, 1601-1622 (2002). doi:10.1002/jcc.10162

Polypeptide and nucleic acid folding

Peptide folding A new method for improved sampling of polymer backbones in Monte Carlo simulations through concerted rotations has been developed. Current applications include folding of peptides and RNA in atomistic detail via MC simulations with a continuum solvent model.

  • Polypeptide Folding using Monte Carlo Sampling, Concerted Rotation, and Continuum Solvation. Ulmschneider, J.P.; Jorgensen, W.L., J. Am. Chem. Soc. 126, 1849-1857 (2004). doi:10.1021/ja0378862
  • Monte Carlo Backbone Sampling for Nucleic Acids using Concerted Rotations including Variable Bond Angles. Ulmschneider, J. P.; Jorgensen, W. L. J. Phys. Chem. B 108, 16883-16892, (2004). doi:10.1021/jp047796z

Water models, force fields, and continuum solvent models

Water dimer Our research group has a leadership position in the development of force fields for organic and biomolecular systems. The TIP3P and TIP4P models of water and the OPLS potential functions are used worldwide. Extension and testing are a continuing process as well as generation of the next level of force fields with explicit treatment of polarization effects. Related areas of research include the use of continuum solvent models and semiempirical partial charges for the calculation of free energies of solvation.

  • Potential energy functions for atomic-level simulations of water and organic and biomolecular systems Jorgensen, W. L.; Tirado-Rives, J. Proc. Nat. Acad. Sci. USA 102, 6665-6670 (2005). doi:10.1073/pnas.0408037102
  • Free Energies of Hydration from a Generalized Born Model and an All-Atom Force Field. Jorgensen, W. L.; Ulmschneider, J. P.; Tirado-Rives, J. J. Phys. Chem. B 108, 16264-16270 (2004). doi:10.1021/jp0484579
  • A five-site model liquid water and the reproduction of the density anomaly by rigid, non-polarizable models. M. W. Mahoney and W. L. Jorgensen, J. Chem. Phys., 112, 8910-8922 (2000). doi:10.1063/1.481505
  • Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids. W. L. Jorgensen, D. Maxwell and J. Tirado-Rives J. Am. Chem. Soc., 118, 11225 (1996). doi:10.1021/ja9621760 (Cited over 600 times)
  • Comparison of Simple Potential Functions for Simulating Liquid Water. W. L. Jorgensen, J. Chandrasekhar, J. D. Madura, R. W. Impey, and M. L. Klein J. Chem. Phys., 79, 926 (1983). doi:10.1063/1.445869. (Cited over 5000 times!)

Research funding

Gratitude is expressed for support from:

  • National Science Foundation
  • NIH, Institute for General Medical Sciences
  • NIH, Institute for Allergy and Infectious Diseases