Our research focuses on atomic-detail computer calculations to examine problems in biochemistry and structural biology. Recent work has focused on the ability of scoring functions based on crystal structures of water-soluble proteins to identify native structures of membrane proteins, algorithms for performing molecular simulations with variable protonation states at constant pH, and for fast calculation of electrostatic forces. Current projects underway include:

1. Mixed quantum-mechanics/molecular mechanics calculations to examine spectral tuning in opsins. These suggest that the most important factor influencing shifts in the absorbance spectrum are the electrostatic potential difference across retinal due to the entire opsin protein.
2. Estimation of ligand-receptor binding affinities: in particular, examining the contribution of conformational change and restriction of conformational freedom of the ligand upon binding; and accounting for proton uptake and release upon binding. Calculations suggest that including a good estimate of the energetic and entropic cost of binding due to the ligand assuming the bound conformation can improve estimation of affinities.
3. Examination of several docking and scoring protocols for estimating binding affinities for a set of 830 ligands to the G&beta₁&gamma₂ subunit, which studies have suggested might be valuable as a target for pharmaceutical development. The best-performing docking protocol used a consensus score and ensemble docking, and resulted in a six-fold enrichment of high-affinity compounds in the top-ranked 5% of the ligand data set.

Figure 1: Crystal Structure of rhodopsin Palczewski et al., Science 289, 739-745 (2000)

Figure 2: Crystal Structure of G&beta₁&gamma₂ subunits, Davis et al., Biochemistry 44, 10593-10604 (2005)