Richard J. Loncharich

The effects of environment and hydration on protein dynamics: A simulation study of myoglobin

Abstract Three classes of molecular dynamics (MD) simulations of carboxy-myoglobin (MbCO) have been performed to investigate the environmental and temperature dependence of protein dynamics. The first class examines the effects of hydration. Simulations of MbCO were performed at 100 and 300 K with 0, 35, 100, 349, and 999 water molecules, and at 300 K with 3832 water molecules. The second class considers a cluster of three partially hydrated MbCO molecules (349 waters each) at 100, 180, 240, and 300 K. The third class of simulations, performed at 100 and 300 K, examines hydration by D2O and also the effects of different vacuum models and long-range electrostatic cutoff methods. The simulations generally consist of 200 ps of heating and equilibration followed by 100 ps of dynamics used for analysis. Atomic fluctuation is compared to neutron scattering data to better determine the type of calculation needed to reproduce the low-temperature behavior of proteins. The simulations of hydrated myoglobin indicate that as the hydration increases: (i) agreement with the X-ray structure improves, (ii) the number of heavy-atom dihedral transitions decreases at both 100 and 300 K, and (iii) atomic fluctuations decrease at 100 K but increase at 300 K. The cluster and deuterated simulations exhibit atomic fluctuations at 100 K similar to, but slightly reduced from, those of a single hydrated myoglobin. Thus, our previous observation from MD simulations of low-temperature mean-square fluctuation three times larger than that observed experimentally does not appear to be due to the mass of the water model, nor the complete absence of intermolecular protein-protein contacts.

Three-dimensional quantitative structure-permeability relationship analysis for a series of inhibitors of rhinovirus replication.

Multiple three-dimensional quantitative structure-activity relationship (3D-QSAR) approaches were applied to predicting passive Caco-2 permeability for a series of 28 inhibitors of rhinovirus replication. Catalyst, genetic function approximation (GFA) with MS-WHIM descriptors, CoMFA, and VolSurf were all used for generating 3D-quantitative structure permeability relationships utilizing a training set of 19 molecules. Each of these approaches was then compared using a test set of nine molecules not present in the training set. Statistical parameters for the test set predictions (r(2) and leave-one-out q(2)) were used to compare the models. It was found that the Catalyst pharmacophore model was the most predictive (test set of predicted versus observed permeability, r(2) = 0.94). This model consisted of a hydrogen bond acceptor, hydrogen bond donor, and ring aromatic feature with a training set correlation of r(2) = 0.83. The CoMFA model consisted of three components with an r(2) value of 0.96 and produced good predictions for the test set (r(2) = 0.84). VolSurf resulted in an r(2) value of 0.76 and good predictions for the test set (r(2) = 0.83). Test set predictions with GFA/WHIM descriptors (r(2) = 0.46) were inferior when compared with the Catalyst, CoMFA, and VolSurf model predictions in this evaluation. In summary it would appear that the 3D techniques have considerable value in predicting passive permeability for a congeneric series of molecules, representing a valuable asset for drug discovery.

Inhibition of human rhinovirus 3C protease by homophthalimides

Abstract Homophthalimides 2a and 3a were found to be inhibitors of Rhinovirus 3C protease through a blind screening effort. SAR studies resulted in compound 3g, which exhibited improved enzyme inhibition, in addition to whole cell antiviral activity. Molecular modeling studies suggest a preferred enzyme/inhibitor interaction, and LC/MS experiments confirmed tight/covalent binding of 3g to the enzyme.

Molecular orbital study of the structure and interactions of ylidene rhodanines

Semiempirical (with the AM1 Hamiltonian) and ab initio (mainly with the 6-31G* and LANL2DZ+ +(d,p) basis sets) molecular oribital calculations show the predominant tautomer of gas phase methylidene rhodanine is 2-thioxo-4-thiazolidinone in agreement with earlier work on other types of rhodanines. Inclusion of solvation effects in the AM1 calculations corroborates with this tautomer is also preferred in aqueous solution. Energy-optimized bond lengths and angles show good agreement with those for a crystalline benzylidene rhodanine. The geometry of a hydrogen bonded dimer matches closely the crystalline state arrangement. The two N-H ⋯ O hydrogen bonds that form in the dimer. provide a stabilization energy of about - 10 kcal/mol. The interactions of methylidene rhodanine with a calcium ion are modeled with basis sets as large as LANL2DZ+ +(d,p). The preferred binding site is near the carbonyl oxygen for the neutral rhodanine and near the nitrogen and thione sulfur in a bidentate arrangement for the rhodanine anion. Implications for the interaction of benzylidene rhodanines with various possible protein and metalloprotein receptors are discussed.