Journal of molecular graphics最新文献

Similarities in the molecular structure and surface properties of the allosteric modulators of muscarinic receptors, alcuronium, gallamine, tubocurarine, and the hexamethonium compound W84, a well-known pharmacological tool, are explored. The analysis of the molecular electrostatic potential (MEP) as well as of the shape of the molecular surface is performed by self-organizing neural networks. A distorted sandwich conformation of W84 is suggested to be the active form. The importance of the MEP for binding of these compounds could be established.

Molecular lipophilicity is a useful property for assessing molecular similarity or complementarity within the context of computer-aided drug design. As well, local contributions to solvent affinity help us to understand both dynamics and conformational stability in biomolecules. In this work, we discuss an approach to characterize the local contributions to hydrophobicity by using one- and two-dimensional representations of molecular channel-like cavities. The method monitors how a phenomenological lipophilicity potential (based on fragmental atom contributions) changes over a continuum of “molecular tubes” used for modeling channels and pores. Our results convey a relatively detailed picture of the spatial distribution of water affinity. The procedure can then be used as a complement to the hydrophobicity scales based on averaging contributions from single amino acids. In addition, we can study how the water affinity changes for inner and outer regious of the pores. As an application, we compute the 3D distribution of lipophilicity in the “pore conformation” of gramicidin A. The qualitative trends indicated by our results are broadly consistent with computer simulations of the gramicidin channel in the presence of hydrated ions. The behavior revealed by the simulations can then be incorporated to produce an improved, simple 2D model for water-channel interactions.

A one-dimensional representation of protein structure in terms of angles between C_αC_α links in a two-dimensional representation describes tertiary structure to an accuracy of approximately 3 Å.

We have developed a cellular automata model of an enzyme reaction with a substrate in water. The model produces Michaelis-Menten kinetics with good Lineweaver-Burk plots. The variation in affinity parameters predicts that, in general, hydrophobic substrates are more reactive with enzymes, this attribute being more important than the relationship between enzyme and substrate. The ease of generation and the illustrative value of the model lead us to believe that cellular automata models have a useful role in the study of dynamic phenomena such as enzyme kinetics.

The structures and molecular properties of 95 aromatic and heteroaromatic ligands previously tested as reversible inhibitors of chymotrypsin catalysis have been calculated using AM1. The properties obtained have been used as input for multiple linear regression analysis and as descriptors for a back-propagation neural network to predict the binding affinity of α-chymotrypsin inhibitors. Using polarizability, molecular shape, electrostatic similarity, dipole moment, ClogP, and the diagonalized quadrupole moments of the ligands, correlation coefficients between calculated and experimental affinities of 0.96 for the training set and 0.89 for the test set were obtained using a neural network. The performance of the multiple linear regression was significantly worse, although useful QSARs were also obtained.

The three-dimensional interaction of the enzyme-activated (suicide) inhibitor AA 231-1 [N(2-chloromethyl)-3,3-difluoro-azetidin-2-one] with human leukocyte elastase has been studied using computer graphics and molecular mechanics. Systematic conformational analyses and energy minimizations have been performed for the inhibitor AA 231-1 and its presumed complexes formed during the enzymatic process of inactivation, i.e., the Michaelis complex, the acyl-enzyme, and the inactivated enzyme with the covalently bound inhibitor. The β-lactam ring characteristics of modeled AA 231-1 were in agreement with crystallo-graphic data of related structures. Lowest energy conformatinos were found when the angle between the planes of the β-lactam ring and that of its phenyl substituent was about −60 or 60°. To study the interaction with the enzyne, the enzyme-inhibitor complexes were constructed by docking the inhibitor in the active site using enzyme coordinates from an X-ray crystallographic structure. The whole enzyme structure was used for conformational analyses and energy mechanics. Favorable conformations for the Michaelis complex have been obtained in which the carbonyl oxygen of the inhibitor was located in the oxyanion hole and the hydroxyl of Ser195 was in position to interact with the β-lactam carbonyl carbon on the α face of AA 231-1. Simulations of the approach of the benzylic carbon by the nucleophilic amino acid His40 or His57 through an S_N2 displacement on the halomethyl group of AA 231-1 were performed. The results agreed with the alkylation of the imidazole nitroge Nϵ2 of His57 leading to the inactivated enzyme (bis-adduct form).

A program has been written that reconstructs three-dimensional coordinates for a protein structure given a stereo C_α diagram. Initial three-dimensional coordinates are determined using an algorithm similar to the one used by Rossmann in the program STEREO. Thereafter the coordinates are refined such that the stereo image based on the reconstructed three-dimensional coordinates optimally fits the scanned stereo image while normal C_α stereochemistry is enforced.