Heather A. Carlson

Professor of Medicinal Chemistry College of Pharmacy

& Professor of Chemistry College of LS&A

University of Michigan, Ann Arbor

MixMD: Development of Accurate Methods for Mapping Protein Surfaces

Mixed-solvent molecular dynamics (MixMD) is a method for mapping protein surfaces using computer simulations of probe molecules and water around the protein. The MixMD approach embraces modeling the protein with full flexibility and allowing competition between probes and water. ”Hotspots” for binding small molecules are identified by regions where the probes interact with the protein more favorably than water does.  Previously, we established the effectiveness of MixMD in reproducing the known binding sites of small organic compounds. Here, I outline our rigorous protocol for the identification of binding hotspots on a protein surface. There are two important requirements: 1) high-ranking hotspots must be mapped at a very high signal-to-noise ratio and 2) the hotspots must be mapped by multiple probes. We have focused our repertoire to include probes that allow us to capture hydrophilic, hydrophobic, hydrogen-bonding, and aromatic interactions. Also, we show that MixMD can identify both competitive and allosteric sites on proteins. To demonstrate the robust nature and wide applicability of the technique, we have applied MixMD to several protein targets.