Computational modeling has played a great role in solving many questions in biochemical and biomedical research. Computers in chemistry are now readily used to study enzymatic reactions, protein-ligand binding, protein folding, macromolecular assembly and other dynamical phenomena. Particularly, in the realm of cell membrane and transmembrane-protein chemistry, computer modeling has provided a great deal of information and guidance. The research presented here in this dissertation furthers the body of work in membrane-protein modeling. The mechanical properties of membranes--tension and lateral pressure--are demonstrated along with the change in these features when a peptide (melittin) is inserted into the membrane. By the simulation technique of umbrella sampling, the thermodynamics of a model hexapeptide (WL5) are probed, as it transverses the span of a membrane. The first free energy calculation of such a system is presented. Coupled with previous experimental findings, a grand model of peptide insertion and aggregation in a membrane host is assembled. Membrane proteins also serve as pharmacological targets in drug discovery. The work presented here focuses on the acetylcholine binding protein (AChBP), a surrogate structure of the nicotinic acetylcholine receptor (nAChR). A virtual screening study was conducted using the relaxed- complex method--in which protein flexibility is captured via a molecular dynamics simulation--of AChBP against a database of ligands from the National Cancer Institute (NCI). The study shows that several small molecule ligands from NCI can bind AChBP and possibly nAChR. Such ligands can serve to differentiate between the three species of AChBP and between the subtypes of the receptor. Furthermore, such ligands can resemble agonistic/ antagonistic behavior of addictive narcotics, thus aiding in counter-drug addiction treatments. A final, peripheral membrane-protein is also studied here; a molecular dynamics simulation of the cytosolic phospholipase A₂ (CPLA2) is conducted, along with a docking study of its known inhibitors. The results are correlated with experimental deuterium exchange data, to afford a broader understanding of protein ligand interactions in this system. As CPLA2 is an important target in pharmacology, this work contributes to the design of novel ligands that can bind appreciably to the enzyme.

An analysis of group IVA (GIVA) phospholipase A(2) (PLA(2)) inhibitor binding was conducted using a combination of deuterium exchange mass spectrometry (DXMS) and molecular dynamics (MD). Models of the GIVA PLA(2) inhibitors pyrrophenone and the 2-oxoamide AX007 docked into the protein were designed on the basis of deuterium exchange results, and extensive molecular dynamics simulations were run to determine protein-inhibitor contacts. The models show that both inhibitors interact with key residues that also exhibit changes in deuterium exchange upon inhibitor binding. Pyrrophenone is bound to the protein through numerous hydrophobic residues located distal from the active site, while the oxoamide is bound mainly through contacts near the active site. We also show differences in protein dynamics around the active site between the two inhibitor-bound complexes. This combination of computational and experimental methods is useful in defining more accurate inhibitor binding sites and can be used in the generation of better inhibitors against GIVA PLA(2).