Theses and Dissertations

Issuing Body

Mississippi State University


Gwaltney, Steven R.

Committee Member

Lewis, Edwin A.

Committee Member

Saebø, Svein

Committee Member

Foster, Stephen C.

Committee Member

Novotny, Mark A.

Date of Degree


Document Type

Dissertation - Open Access



Degree Name

Doctor of Philosophy


College of Arts and Sciences


Department of Chemistry


The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are inhibited by nerve agents such as sarin and tabun. In general, the inhibited enzymes are reactivated by bisquaternary ammonium compounds (oximes). The binding free energies of the oximes; 2-PAM, MMB-4, HI-6, and obidoxime bound to human AChE (hAChE) and human BChE (hBChE) inhibited by sarin and tabun and also to the uninhibited enzymes were calculated using various computational methods. Using thermodynamic integration, the binding free energies of all the inhibited and uninhibited systems of MMB-4 and obidoxime were evaluated. The standard binding free energies (dA) were more negative than the experimental values due to limitations of the ff99 forcefield. The RMS error of dA for the inhibited systems of MMB-4 was 2.1 kcal/mol, and for obidoxime systems it was 4.8 kcal/mol with respect to the experimental free energies. The binding enthalpies calculated using MM-GBSA and MM-PBSA methods for 2-PAM, MMB-4, HI-6, and obidoxime systems were negative, except for hBChE-sarin-MMB-4 and hBChE-sarin-obidoxime. For all the systems the TdS values calculated using normal mode analysis were equal to or lower in magnitude than their corresponding binding enthalpies. As a result, the estimated free energies were positive for most of the systems. Clearly, the present algorithms cannot effectively estimate the binding entropies for a protein-ligand system. Met81 has commonly shown favorable interactions, and lysine or arginine exhibited unfavorable interactions with the reactivator in all the systems. Second, the interactions between chloropyrifos-oxon (Cpo) and experimentally tested neutral and monopyridinium oximes bound to the Q192 or R192 polymorphs of human paraoxonase1 (hPON1) were studied. The equilibrated Q192 and R192 hPON1 were structurally different than the crystal structure of recombinant PON1. The neutral oximes have shown more favorable interactions with Cpo in Q192 hPON1 + Cpo system compared to R192 hPON1 + Cpo. Whereas the monopyridinium oximes interacted more affectively with Cpo in R192 hPON1 than Q192 hPON1. The relative deprotonation energy of the monopyridinium oxime was lower than the neutral oxime. Hence, the monopyridinium oxime can hydrolyze an organophosphate at a higher rate than a neutral oxime.