News and Publications

Biological Applications of Computational Chemistry

J.D. Hirst, C.L. Brooks III, N. Besley, P. Constans

QUANTUM CHEMISTRY

The amide bond is the fundamental constituent of proteins. Consequently, knowledge of the optical properties of this bond is key to understanding the absorption and circular dichroism spectra of proteins. Development of this knowledge requires a theoretical description of the electronic states of amides. Using a reaction field to model solvent effects, we recently completed electronic ground and excited state calculations on a series of small amides. These calculations have provided us with the most reliable description to date of the electronic excited states of amides in solution. Figure 1 shows the influence of solvent on the first electronic excited state. Large solvent effects result in a large destabilization of the diffuse atomic-like Rydberg states, and in a small solvent cavity, such states are not observed. We are assessing the applicability of these charge distributions in calculations of the circular dichroism of proteins. This work is an exciting bridge between state-of-the-art quantum chemical methods and the understanding of an important biophysical phenomenon.

CIRCULAR DICHROISM OF PROTEINS

Circular dichroism spectroscopy is one of the most widely used analytical tools in the study of protein structure and folding. It provides a coarse measure of the secondary structure of a protein in solution. We are developing the theoretical basis of circular dichroism to further our understanding of how protein conformation determines the circular dichroism spectra. Circular dichroism arises from the electronic transitions of chiral compounds.

We are using quantum chemistry calculations to investigate the electronic absorption spectra of small amides. In parallel with the ab initio approach, we are also investigating an empirical derivation of parameters to describe the electronic states of the amide chromophore. These parameters will be used to develop a quantitative method to calculate the circular dichroism of given protein structures and thus provide the connection between the atomic-detailed structure of proteins and their circular dichroism spectra.

COMPUTER-AIDED DRUG DESIGN

The advent of combinatorial chemistry technologies demands the development of fast and accurate quantitative structure-activity relationships, with the goal of directing the robotic synthesis of compounds in real time. We have developed a fast and reliable method for deriving nonlinear quantitative structure-activity relationships. We are extending this work to investigate other nonparametric methods, such as smoothing regression techniques. Efficiency will be a key issue for the analysis of data sets of thousands of molecules.

PUBLICATIONS

Hirst, J.D. Improving protein circular dichroism calculations in the far-ultraviolet through reparameterizing the amide chromophore. J. Chem. Phys., in press.

Hirst, J.D. Improving protein circular dichroism calculations through better ab initio models of the amide chromophore. Enantiomer, in press.

Hirst, J.D. Predicting ligand binding energies. Curr. Opin. Drug Des. Dev., in press.

Hirst, J.D. Theoretical studies of the circular dichroism of proteins. Recent Res. Dev. Phys. Chem., in press.

Hirst, J.D., Dominy, B., Guo, Z., Vieth, M., Brooks, C.L. III. Conformational and energetic aspects of receptor-ligand recognition. Am. Chem. Soc. Symp. Ser., in press.

Vieth, M., Hirst, J.D., Brooks, C.L. III. Do active site conformations of small ligands correspond to low free energy solution structures? J. Comput. Aided Mol. Des., in press.

Vieth, M., Hirst, J.D., Dominy, B.N., Daigler, H., Brooks, C.L. III. Assessing search strategies for flexible docking. J. Comp. Chem., in press.

Vieth, M., Hirst, J.D., Kolinski, A., Brooks, C.L. III. Assessing energy functions for flexible docking. J. Comp. Chem., in press.