Our group develops new computational methods to study biophysical chemistry, including topics like as membrane permeation, ion-biomolecule binding, and the covalent modification of proteins. In this talk, I will present examples of our recent work on these topics. The first topic is the permeation of gasotransmitters through cell membranes. H2S, CO, and NO are endogenous signaling molecules with potential to be used as anti-inflammatory agents. These molecules are able to permeate cell membranes rapidly without a facilitator. Our simulations show that the small radii and hydrophobicity of these molecules allow them to diffuse freely through membranes, allowing them to react with intracellular targets rapidly . Using a polarizable force field and a model derived from the Generalized Langevin Equation, we were able to predict the rate of permeability quantitatively. Our next subject was the relative solubility of Mg(II) and Zn(II). QM/MM simulations reveal that the greater Lewis acidity of Zn(II) results in its greater solubility. Lastly, we have studied drugs that contain cysteine-targeting electrophiles that form covalent bonds with their targets. A new class of kinase-targeting anti-cancer drugs (e.g. ibrutinib) include an electrophilic acrylamide group that reacts with an active site cysteine residue. By computationally screening hundreds of putative warheads, we found that effective warheads must allow for slow and reversible additions, which avoids non-selective modification of proteins. We have also developed a new computational method to identify acidic cysteine residues that serve as facile targets for covalent modification .
 Riahi, S., Rowley C.N. Why Can Hydrogen Sulfide Permeate Cell Membranes? J. Am. Chem. Soc. 2014, doi: 10.1021/ja508063s
 Riahi, S., Rowley C.N. J. Comput. Chem. 2014, doi: 10.1002/jcc.23716  Awoonor-Williams, E., Rowley, C.N. J. Chem. Theory Comput., 2016, doi: 10.1021/acs.jctc.6b00631
Asst. Prof. Jesse G. McDaniel (firstname.lastname@example.org)