Specific Noncovalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small-Molecule CD4 Mimetics and HIV-1 gp120.

The small-molecule CD4 mimetics (smCD4mcs) are a class of highly potent HIV-1 entry inhibitors characterized by a unique structure-activity relationship (SAR). They share a halogenated phenyl ring (region 1) that deeply inserts into an otherwise water-filled cavity at the CD4 binding site on the gp120 surface, the so-called F43 cavity. Conservative modifications to region 1 away from this halogenated phenyl motif have all led to loss of activity, despite the fact that they are predicted by standard empirical computational approaches to bind equally well, making it difficult to further optimize this region of the compounds to increase binding to gp120.

Automated Transition State Search and Its Application to Diverse Types of Organic Reactions.

Transition state search is at the center of multiple types of computational chemical predictions related to mechanistic investigations, reactivity and regioselectivity predictions, and catalyst design. The process of finding transition states in practice is, however, a laborious multistep operation that requires significant user involvement. Here, we report a highly automated workflow designed to locate transition states for a given elementary reaction with minimal setup overhead.

Extension of QM/MM docking and its applications to metalloproteins.

To overcome the limitation of conventional docking methods which assume fixed charge model from force field parameters, combined quantum mechanics/molecular mechanics (QM/MM) method has been applied to docking as a variable charge model and shown to exhibit improvement on the docking accuracy over fixed charge based methods. However, it has also been shown that there are a number of examples for which adoption of variable-charge model fails to reproduce the native binding modes. In particular, for metalloproteins, previously implemented method of QM/MM docking failed most often.

Density functional localized orbital corrections for transition metals.

This paper describes the development of the B3LYP localized orbital correction model which improves the accuracy of the B3LYP thermochemical predictions for compounds containing transition metals. The development of this model employs a large data set containing 36 experimental atomic energies and 71 bond dissociation energies. B3LYP calculations were carried out on these systems with different basis sets.

Intermediates in dioxygen activation by methane monooxygenase: a QM/MM study.

Protein effects in the activation of dioxygen by methane monooxygenase (MMO) were investigated by using combined QM/MM and broken-symmetry Density Functional Theory (DFT) methods. The effects of a novel empirical scheme recently developed by our group on the relative DFT energies of the various intermediates in the catalytic cycle are investigated. Inclusion of the protein leads to much better agreement between the experimental and computed geometric structures for the reduced form (MMOH(red)).

A computational study of the open and closed forms of the N-lobe human serum transferrin apoprotein.

Human serum transferrin tightly binds ferric ions in the blood stream but is able to release them in cells by a process involving receptor-mediated endocytosis and decrease in pH. Iron binding and release are accompanied by a large conformation change. In this study, we investigate theoretically the open and closed forms of the N-lobe human serum transferrin apoprotein by performing pKa calculations and molecular dynamics and free-energy simulations.