In my research, quantum mechanics, statistical mechanics, molecular mechanics, and database mining techniques are used to investigate chemical and enzymatic systems of biomedical importance. Structure-function relationships and enzymatic regulation often result from subtle details at the atomic level; this detail is beyond the scope of current experimental methods for biological systems. Understanding enzymatic control allows us to explain the mechanism of disease and suggest routes for inhibition. Our research focuses primarily on protein-ligand recognition, protein flexibility, and new methods for computer-aided drug discovery.
One of the major projects in my lab is the development of a method for incorporating protein flexibility into the drug design process. A particular breakthrough with this method is that unbound, apo protein structures can be successfully used in drug design. If the community does not need to wait for ligand-bound crystal structures, we can tackle important systems years earlier than previously possible. This research is funded by the NIH.
The other major project in the lab is the continued curration of the largest database of protein-ligand complexes: Binding MOAD (Mother of All Databases) and CSAR (Community Structure-Activity Resource). MOAD continues to grow with the PDB, and CSAR is developed with depositions of protein-ligand data from the pubic and private sectors. Websites for CSAR are coming soon. MOAD is currently available online (www.BindingMOAD.org), and we continue to develop web-based tools that allow other users to pull information from our dataset. The patterns within this dataset allow us to better understand the molecular recognition behind ligand-binding events. This research is funded by the NSF and NIH.
Schuyler AD, Carlson HA, Feldman EL. Computational methods for predicting sites of functionally important dynamics. J. Phys. Chem. B 2009, 113, 6613-6622.
Lexa KW, Damm KL, Quintero JJ, Gestwicki JE, Carlson HA. Clarifying allosteric control of flap conformations in the 1TW7 crystal structure of HIV-1 protease. Proteins 2009, 74, 872-880.
HA Carlson, RD Smith, NA Khazanov, PD Kirchhoff, JB Dunbar Jr., ML Benson. Fundamental differences between high- and low-affinity complexes of enzymes and non-enzymes. J. Med. Chem. 2008, 51, 6432-6441.
KL Damm, PMU Ung, JJ Quintero, JE Gestwicki, HA Carlson. A poke in the eye: Inhibiting HIV-1 protease through its flap-recognition pocket. Biopolymers 2008, 89, 643-652. (Highlighted on the journal's cover, on the NIGMS website, and several news outlets)
Lerner MG, Meagher KL, Carlson HA. Automated clustering of probe molecules from solvent mapping of protein surfaces: new algorithms applied to hot-spot mapping and structure-based drug design. J. Comput. Aided Mol. Des. 2008, 22, 727-736.
ML Benson, RD Smith, NA Khazanov, B Dimcheff, J Beaver, P Dresslar, JE Nerothin, HA Carlson. Binding MOAD, a high-quality protein-ligand database. Nucleic Acids Res. 2008, 36, D674-D678.
AL Bowman, Z Nikolovska-Coleska, H Zhong, S Wang, HA Carlson. Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models. J. Am. Chem. Soc. 2007, 129, 12809-12814.
KL Damm, HA Carlson. Exploring experimental sources of multiple protein conformations in structure-based drug design. J. Am. Chem. Soc. 2007, 129, 8225-8235. (Highlighted in Nature’s news blog)