Lipoxygenases (lox) are a group of non-heme iron containing enzymes that catalyze oxygenation of poly-unsaturated fatty acids with precise regio- and stereo-selectivity. The origin of regio- and stereo-specific catalysis by 8-lox is explored in its wild-type (wt) form and in three mutants (Arg185Ala, Ala592Met, and Ala623His). The catalytic action of this enzyme progresses in two steps, namely, hydrogen abstraction from one double allylic carbon atom of substrate followed by oxygen insertion at the resulting prochiral carbon radical of the substrate. It is shown that the positional specificity of the hydrogen abstraction is a result of conformational dynamics of the bound substrate. While C10 atom of the substrate is found to be the most probable site of hydrogen abstraction in the wt-lox, hydrogen abstraction from C13 is more favorable in the mutants. The present study discovers the presence of an inter-connected network of three-channel migration pathway operating in the protein matrix for efficient oxygen transport. Each migration channel is bestowed with a pocket at the peripheral region of protein as oxygen access site, which transfers the oxygen to the active site through a well connected migration path in a time scale of a few hundred picoseconds. By a careful geometric analysis of the oxygen pockets near the substrate binding cleft, the present study identifies the launching sites for oxygenation at the prochiral carbon centers C8, C11, C12, and C15 and the stereochemistry (R\/S) of the corresponding products. It is found that dominating 8R product in the wt-lox is due to the presence of the aromatic ring pair of Tyr181 and Phe173 acting gate-keeper for efficient delivery of oxygen at the pro-R face of C8. The change in the stereochemistry of the products in mutants is explained in terms of dynamic interactions between substrate and the surrounding residues.<\/p>")"> Abstract

(PMe3)2FeCl3 is an Fe(III) complex that exists in the intermediate-spin ground state in a distorted trigonal bipyramidal geometry. An electronic state with high-spin configuration lies in close vicinity to the ground state, making it a potential spin crossover candidate. A mechanistic account of the spin crossover from the lowest quartet state (Q0) to the lowest sextet state (S1) of this complex is provided by exploring both thermal and light-induced pathways. The presence of a large barrier between the two spin states suggests a possible thermal spin crossover at a rather high temperature. The light-induced spin crossover is investigated by employing complete active space self-consistent field calculations together with dynamic correlation and spin–orbit coupling for the lowest seven quartet and lowest five sextet states. The system in the Q0 state upon light absorption is excited to the optically bright Q4 LMCT state. By following minimum energy pathways along the electronic states, two light-induced pathways for spin crossover are identified. From the Q4 state, the system can photo-regenerate the ground intermediate-spin state (Q0) through an internal conversion of Q4\/Q3 followed by Q3\/S1 and S1\/Q0 intersystem crossings. In an alternate route, through Q4\/S2 intersystem crossing followed by S2\/S1 internal conversion, the system can complete the spin crossover from the Q0 to S1 state.<\/p>")"> Abstract

The Renner vibronic-coupling problem in 4Π electronic states of linear molecules is analyzed with rigorous and systematic inclusion of spin-orbit (SO) coupling. The 8 × 8 Hamiltonian matrix of a 4Π state in the diabatic electronic representation has been constructed by a Taylor expansion in the bending normal mode up to second order. As previously found for 2Π states and 3Π states, SO-induced vibronic-coupling terms that are linear in the bending amplitude exist in addition to the quadratic electrostatic Renner coupling. The effects of the linear and quadratic Renner coupling on the four Kramers-degenerate potential energy surfaces of the 4Π state are discussed. The spectroscopic effects of the linear SO-vibronic-coupling mechanism have been analyzed by numerical calculations of vibronic spectra.<\/p>")"> Abstract

In the era of ever-increasing anti-microbial resistance, drug re-purposing offers a faster and economic route to the discovery of novel antibiotics. L-Captopril, a widely used angiotensin-converting enzyme inhibitor, has shown inhibitory action towards the microbial enzyme DapE, which is a potential antibiotic target. In this work, a series of biased and unbiased QM\/MM-MD simulations has been carried out to investigate the catalytic hydrolysis of L-captopril along a general acid-base hydrolysis mechanism. The QM\/MM-MD simulations not only provide an accurate estimation of free energy of activation, but also account for the corrections to the free energy arising from conformational dynamics of the enzyme-substrate complexes. The nucleophilic attack of the hydroxyl ion on the carbonyl group of L-captopril, was found to be the rate-determining step of the catalyzed hydrolysis reaction, which involved activation energy barrier of 15.6 and 13.1 kcal\/mol, for the O- and S-coordinated conformations of L-captopril, respectively. Comparing these activation energy barriers with the barriers obtained for the hydrolysis of the natural substrate of DapE enzyme, it is concluded that the catalytic activation of L-captopril by DapE is as efficient as the activation of its natural substrate. Unlike the natural substrate, the activation of L-captopril by DapE yields side products that interrupt the crucial lysine biosynthetic pathway in bacteria.<\/p>\r\n\r\n

 <\/p>")"> Abstract

The amyloid cascade hypothesis dealing with the senile plaques is until date thought to be one of the causative pathways leading to the pathophysiology of Alzheimer’s disease (AD). Though many aggregation inhibitors of misfolded amyloid beta (Aβ<\/em>42) peptide have failed in clinical trials, there are some positive aspects of the designed therapeutic peptides for diseases involving proteinaceous aggregation. Here, we evaluated a smart design of side chain tripeptide (Leu-Val-Phe)-based polymeric inhibitor addressing the fundamental hydrophobic amino acid stretch “Lys-Leu-Val-Phe-Phe-Ala” (KLVFFA) of the Aβ<\/em>42 peptide. The in vitro analyses performed through the thioflavin T (ThT) fluorescence assay, infrared spectroscopy, isothermal calorimetry, cytotoxicity experiments, and so on evinced a promising path towards the development of new age AD therapeutics targeting the inhibition of misfolded Aβ<\/em>42 peptide fibrillization. The in silico simulations done contoured the mechanism of drug action of the present block copolymer as the competitive inhibition of aggregate-prone hydrophobic stretch of Aβ<\/em>42.<\/p>")"> Abstract