My group undertakes research in the area of computational biophysics.  There have been three major foci in my group; our most important contributions in each of these areas are summarized below.  Links are provided to relevant papers.

Computer-aided drug design

Over the past several years, my most impactful work in the area of drug design has been on membrane permeability (including gut absorption and the blood-brain barrier), and the computer-aided design of cell-permeable and orally bioavailable macrocycles (for challenging targets like protein-protein interfaces and allosteric sites).  In collaboration with Scott Lokey (UC Santa Cruz), my group did pioneering work in both of these areas, and our work has generated a great deal of interest in the pharmaceutical industry.  Our important early contribution, which has only recently started to attract a high level of attention, was

T. Rezai, J. E. Bock, M. Vong, C. Kalyanaraman, R. S. Lokey, and M. P. Jacobson.  “Conformational Flexibility, Internal Hydrogen Bonding, and Passive Membrane Permeability:  Successful In Silico Prediction of the Relative Permeabilities of Cyclic Peptides”, JACS, 128 (2006) 14073–14080.

We have published a number of additional papers in this arena, including several subsequent methodological advances (especially publications #98), but the highest profile work is contained in this paper, which describes the design of orally bioavailable, purely synthetic cyclic peptide macrocycles:

T. R. White, C. M. Renzelman, A. C. Rand, T. Rezai, C. M. McEwen, V. M. Gelev, R. A. Turner, A. C. Rand, R. G. Linington, S. S. F. Leung, A. S. Kalgutkar, J. N. Bauman, Y. Zhang, S. Liras, D. A. Price, A. M. Mathiowetz, M. P. Jacobson, and R. S. Lokey. “On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds“, Nature Chemical Biology, 7 (2011) 810-817.

We also use methods of computer-aided drug design in academic and industrial collaborations, including productive long-term collaborations with the McKerrow lab on infectious diseases, with the Prusiner lab on prion disease, and with Pfizer in several areas.

New approaches to enzyme function prediction

Starting in 2005, my group played a major role in developing new structure-based approaches to enzyme function prediction, leveraging the computational methods that we and others have developed for drug design, i.e., metabolite docking instead of inhibitor docking.  This line of research has been highly productive over the past few years, with two papers in Nature and two in PNAS in 2012-2013 alone.  In the most recent paper, my postdoc Suwen Zhao predicted a novel catabolic pathway, containing new enzymatic reactions and new metabolites, all of which were fully confirmed experimentally.

S. Zhao, R. Kumar, A. Sakai, M. Vetting, B. M. Wood, S. Brown, P. C. Babbitt, S. C. Almo, J. V. Sweedler, J. A. Gerlt, J. E. Cronan, and M. P. Jacobson.  “Discovery of new enzymes and metabolic pathways using structure and genome context“, Nature, 502 (2013) 698-702.

Atomically Detailed Mechanisms of Protein Regulation

The early goal of this project was to better understand and predict how phosphorylation modulates the energy landscapes of proteins, driving changes in conformation and dynamics, which in turn can modulate function. This work has broadened to incorporate other post-translational modifications (Lys acetylation and succinylation, with Eric Verdin’s group at the Gladstone), pH regulation (with Diane Barber and Mark Kelly), and allosteric ligand binding.