Welcome to the Merz Research Group
We are involved in research at the interface between the computational sciences and biology. We work on a number of problems and collaborate with experimentalists at every opportunity. Research areas of most interest include computer-aided drug design (CADD), using the Movable Type method to compute free energies, enthalpies and entropies of biological processes, metalloenzymes and metal ion homeostasis, development and application of linear-scaling quantum mechanical methods to biological problems and NMR and X-ray structure refinement using classical and quantum mechanical methods. For further details go to the research section and look over our publications.
Using Ligand Induced Protein Chemical Shift Perturbations to Determine Protein-ligand Structure
Protein chemical shift perturbations (CSPs), upon ligand binding, can be used to refine the structure of a protein-ligand complex by comparing experimental CSPs with calculated CSPs for any given set of structural coordinates. We recently describe a fast and accurate methodology that opens up new opportunities to improve the quality of protein-ligand complexes using nuclear magnetic resonance (NMR) based approaches by focusing on the effect of the ligand on the protein. The new computational approach, 1H empirical chemical shift perturbation (HECSP), rapidly calculates ligand binding induced CSPs for both the backbone and sidechain protons in a protein. Given the dearth of experimental information by which a model could be derived we employed high-quality DFT computations using the automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) approach to derive a database of ligand induced CSP’s on a series of protein-ligand complexes. Overall, the empirical HECSP model yielded correlation coefficients between its predicted and DFT computed values of 0.897 (1HA), 0.971 (1HN) and 0.945 (sidechain 1H) with root-mean-square errors (RMSEs) of 0.151 (1HA), 0.199 (1HN) and 0.257 ppm (sidechain 1H), respectively. Using the HECSP model, we also developed a scoring function (NMRScore_P) that can refine complex structures using experimental CSP information. The results of studies on the apo-Neocarzinostatin (apoNCS)-naphthoate and human intestinal fatty acid binding protein (hIFABP)-ketorolac-ANS systems demonstrate that an NMRScore_P strategy for protein-ligand complexes, which is built upon HECSP, can be readily applied to solution NMR structures. In particular, we show the method can distinguish native ligand poses from decoys and refine protein-ligand complex structures. We provide further refined models for both complexes, which satisfy the experimental 1H CSPs. The software to carry out the calculations can be found in the software section (under HECSP) of this web page.