The protonation state of the catalytic aspartates of HIV-1 protease (HIVPR) is atypical and as a result is the subject of much debate. Modeling of the correct protonation state of the aspartates is vital in computational drug design. Using pH replica-exchange molecular dynamics, we simulated the apo and bound forms of HIV-1 protease with 12 different protease inhibitors to investigate the pKa of not only the catalytic dyad but also the other titrating residues in HIVPR. The results obtained from these simulations are compared to experiment where possible. This study provides evidence that the catalytic aspartates are primarily in a monoprotonated state for both the apo and bound forms of HIVPR in the pH range where generally most experiments and computational simulations occur.

Storage, synthesis, and application of energetic materials is significantly impacted by the fundamental property of sensitivity. The method of storage and handling is affected by the sensitive nature of the explosive. Possessing the ability to predict the sensitivity of energetic material candidates before expensive synthesis is begun would be an asset. Also, predicting the applications of various energetic compounds before synthesis and testing can be made possible with the aid of sensitivity predictions. Quantum mechanical methods are applied to approximating the heat of detonation. Correlation between heat of detonation and impact sensitivity is examined.

Structure‐activity relationship (SAR) studies of the natural pesticidal peptide, tentoxin, are described in the context of similarity between pharmaceutical and agricultural methods of developing biologically active peptidomimetics. Essential residue substitutions that confer biological activity through predictable conformational changes in the peptide backbone and side chain functionalities are discussed. A combination of molecular modelling studies and the biological activity of natural, synthetic and photochemically transformed analogs of tentoxin is utilized to further the understanding of structural and conformational requirements for biological activity.

Estrogen receptors (ER) are known as nuclear receptors. They exist in the cytoplasm of human cells and serves as a DNA binding transcription factor that regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding. The human estrogen receptor comes in two forms, alpha and beta. This work focuses on the alpha form of the estrogen receptor. The ERα is found in breast cancer cells, ovarian stroma cells, endometrium, and the hypothalamus. It has been suggested that exposure to DDE, a metabolite of DDT, and other pesticides causes conformational changes in the estrogen receptor. Before examining these factors, this work examines the protein unfolding from the antagonist form found in the 3ERT PDB crystal structure. The 3ERT PDB crystal structure has the estrogen receptor bound to the cancer drug 4-hydroxytamoxifen. The 4-hydroxytamoxifen ligand was extracted before the simulation, resulting in new conformational freedom due to absence of van der Waals contacts between the ligand and the receptor. The conformational changes that result expose the binding clef of the co peptide beside Helix 12 of the receptor forming an apo conformation. Two key conformations in the loops at either end of the H12 are produced resulting in the antagonist to apo conformation transformation. The results were produced over a 42ns Molecular Dynamics simulation using the AMBER FF99SB force field.

No abstract