Determination of the optimal position of adjacent proton-donor centers for the activation or inhibition of peptide bond formation--a computational model study.

The study reports a computational analysis of the influence of proton donor group adjacent to the reaction center during ester ammonolysis of an acylated diol as a model reaction for peptide bond formation. This analysis was performed using catalytic maps constructed after a detailed scanning of the available space around the reaction centers in different transition states, a water molecule acting as a typical proton donor. The calculations suggest that an adjacent proton donor center can reduce the activation barrier of the rate determining transition states by up to 7.

Catalytic role of vicinal OH in ester aminolysis: proton shuttle versus hydrogen bond stabilization.

This computational study provoked by the process of peptide bond formation in the ribosome investigates the influence of the vicinal OH group in monoacylated diols on the elementary acts of ester aminolysis. Two alternative approaches for this influence on ester ammonolysis were considered: stabilization of the transition states by hydrogen bonds and participation of the vicinal hydroxyl in proton transfer (proton shuttle). The activation due to hydrogen bonds of the vicinal hydroxyl via tetragonal transition states was rather modest; the free energy of activation was reduced by only 5.

Hierarchical approach to conformational search and selection of computational method in modeling the mechanism of ester ammonolysis.

We describe automated procedures for the first stages of a systematic computational investigation of reaction mechanisms. They include (i) selection of computational method and basis set based on statistical analysis of structural and energy data relating to experimental values, (ii) determination of all distinct conformations of transition states with large conformational freedom, and (iii) generation of unknown geometry of the transition states, based on pre-defined connectivity of the atoms involved in the reaction. For the conformational search we employed an efficient procedure for exploration of various possible conformations of the transition states and elimination of the equivalent structures in several steps using molecular-mechanical and quantum-mechanical methods.

Selective silencing of DNA-specific B lymphocytes delays lupus activity in MRL/lpr mice.

The pathological DNA-specific B lymphocytes in lupus are logical targets for a selected therapeutic intervention. We have hypothesized that it should be possible to suppress selectively the activity of these B cells in lupus mice by administering to them an artificial molecule that cross-links their surface immunoglobulins with the inhibitory FcgammaIIb surface receptors. A hybrid molecule was constructed by coupling the DNA-mimicking DWEYSVWLSN peptide to a monoclonal anti-mouse FcgammaRIIb antibody.