Research — Mark R. Ams

We do organic chemistry research in the Ams Lab, and our focus is on investigating how molecules are attracted to each other. This is a fundamental aspect of the field of molecular recognition, and of critical importance in areas such as drug discovery and design. There is still much left to learn, and we take an experimental approach to the challenge by designing and synthesizing organic molecules that will help us understand the forces that govern intermolecular interactions.

Project 1: Expanding chemical space

Next-generation molecular building blocks with multifunctional properties are in high demand for increasing the diversity and functionality of supramolecular architectures. We are working on a new class of building blocks based on chalcogen bonding interactions that may expand the current supramolecular toolkit by achieving two goals simultaneously: (1) expanding intermolecular connections while (2) providing secondary functions. These goals have implications for information storage, supramolecular chemistry, and optoelectronics. Our building block is based on 2,1,3-benzothiadiazole (BTD) derivatives, and we are developing hetero-square BTDs using solid- and solution-phase techniques (Figure. 1).

**Figure 1.** A) Top view showing the in-plane position of the nitrogen lone pairs, sulfur sigma-holes and sigma-star orbitals. B) Homo- and C) hetero-square dimers.

Project 2: Halogen behavior in hydrophobic pockets

Halogen’s ability to enhance CH●●●pi contacts is an under-explored research area, yet many drugs contain alkyl halides and have this interaction within their binding pockets. We recently searched the Protein Data Bank for ligands involved in XC—H●●●pi contacts, and found that F and Cl are prevalent with aromatic amino acids (Figure 2A-B). We use torsion balance molecules to mimic and quantify these contacts in solution (Figure 2C). In 2015 we learned that FC—H●●●pi contacts can be stronger than their non-halogenated counterparts, and we are currently evaluating Cl. Our short-term goal is identifying strong (F/Cl)C—H●●●pi combinations, and our long-term objective is to apply this information toward the development of new drug candidates.

**Figure 2.** Protein-drug interactions that contain A) FC—H●●●pi and B) ClC—H●●●pi contacts. C) Our torsion balance molecule.

Project 3: Quantifying bound-state entropy

Quantifying the residual motion in a weakly bound state provides a unique opportunity for chemists to better understand the origins of Gibbs Free Energy values. That is to say, the fundamental enthalpy-entropy compensation that drives binding. Many drugs currently under investigation and on the market today are fluorinated or chlorinated (Figure 3). The principles we learn about residual motion within bound states may be directly applicable to such systems, as well as to current computational models that are in need of improvement.

**Figure 3.** Examples of alkyl fluorinated or chlorinated drug-protein complexes.

We are currently using torsion balance molecules to along with 19F-NMR spectroscopy to determine the populations of microstates that exist when organofluorine fragments are buried within a hydrophobic cleft (Figure 4.). Our goal is to determine what role bound-state entropy has in influencing the Gibbs Free Energy of binding.