QM/MM study of the stereospecific proton exchange of glutathiohydroxyacetone by glyoxalase I

We have performed quantum mechanics (QM), molecular mechanics (MM) and hybrid QM/MM calculations to study the stereospecific proton exchange of glutathiohydroxyacetone (HOC-SG) by glyoxalase I (GlxI). We did the QM/MM calculations with a large QM system (246 atoms) to investigate the proton-exchange mechanism. Moreover, single-point big-QM energies with 1303 atoms in the big QM system and 22,412 atoms in the MM sys- tem were used to compare the energy difference of the stationary structures. GlxI catalyzes the exchange of the pro-S, but not the pro-R hydroxymethyl proton of HOC-SG with a deuterium from the D2O solvent. Classical mo- lecular dynamics simulations with different protonation states of Glu99, Glu172 and HOC-SG led to the determi- nation of most stable species (Glu-172 is protonated and the alcoholic oxygen of HOC-SG is deprotonated). The QM/MM results showed that before binding of HOC-SG, both active-site glutamates are charged, whereas HOC- SG is protonated. When HOC-SG binds, its alcoholic proton (HO) can point toward either Glu-99 or Glu-172. How- ever, if the substrate binds so that HO is directed toward Glu-99, it is not transferred, whereas if it is directed to- ward Glu-172, the latter abstracts HO. The results showed that transferring HO to the glutamates from the reactant states is the key step to make the proton exchange reaction possible. Our calculations show that order of basicity of the glutamates and HOC-SG inside the enzyme is: Glu-172 N HOC-SG N Glu-99. The calculations allow us to propose a reaction mechanism for the stereospecific proton exchange of HOC-SG by GlxI with an over- all barrier of 14.1 kcal/mol

Relationship between Corporate Governance and CEO Compensation among Listed Firms in Tehran Stock Exchange

This study aims to investigate the relationship between corporate governance and executives' compensation. This is semi-empirical study and statistical sample of research was 95 companies listed in Tehran stock exchange from 2010 to 2014. Variables ratio of non-executive board members, dichotomy of managing director responsibility, ownership of institutional shareholders and managerial ownership were considered as independent variables. Factors influencing executives' compensation were considered and the relationship between these variables was studied using multivariate regression. Findings show that there is significant relationship between duty of managing director, ownership of institutional investors and managerial ownership. However, there was no evidence for significant relationship between ratios of non-executive board members with executives' compensation. Keywords: executives' compensation, ratio of non-executive board members, dichotomy of managing director responsibility, ownership of institutional investors, managerial ownership JEL Classifications: G34, J

Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I

Glyoxalase I (GlxI) is a member of the glyoxalasesystem, which is important in cell detoxification and convertshemithioacetals of methylglyoxal (a cytotoxic byproduct of sugarmetabolism that may react with DNA or proteins and introducenucleic acid strand breaks, elevated mutation frequencies, andstructural or functional changes of the proteins) and glutathioneinto D-lactate. GlxI accepts both the S and R enantiomers ofhemithioacetal, but converts them to only the S-D enantiomer oflactoylglutathione. Interestingly, the enzyme shows this unusualspecificity with a rather symmetric active site (a Zn ioncoordinated to two glutamate residues; Glu-99 and Glu-172),making the investigation of its reaction mechanism challenging.Herein, we have performed a series of combined quantummechanics and molecular mechanics calculations to study the reaction mechanism of GlxI. The substrate can bind to the enzyme in two different modes, depending on the direction of its alcoholic proton (H2; toward Glu-99 or Glu-172). Our results show that the S substrate can react only if H2 is directed toward Glu-99 and the R substrate only if H2 is directed toward Glu-172. In both cases, the reactions lead to the experimentally observed S-D enantiomer of the product. In addition, the results do not show any low- energy paths to the wrong enantiomer of the product from neither the S nor the R substrate. Previous studies have presented several opposing mechanisms for the conversion of R and S enantiomers of the substrate to the correct enantiomer of the product. Our results confirm one of them for the S substrate, but propose a new one for the R substrate

Biologic characteristics of platelet rich plasma and platelet rich fibrin : A review

The recent development of platelet concentrate for surgical use is an evolution of the fibrin glue technologies used since many years. Fibrin is a biologic glue that compact platelet clusters during coagulation process fibrin glues are biologic products that their local application has been used to decrease bleeding and accelerate tissue healing in the past three decades. Fibrin glue prepared based on a natural biologic mechanism (polymerization of fibrin during homeostasis) that reinforced by an artificial way. However, they were ever criticized because were blood derived products and had a high risk of viral infection the production of these products is based on the mixture of two plasma components including fibrinogen and thrombin. Platelet-rich plasma (PRP) is a fibrin matrix in which platelet cytokines, growth factors, and cells are trapped and may be released after a certain time. Choukroun et al. used platelet rich fibrin (PRF) protocol in oral and maxillofacial surgery to improve bone healing. Autologous PRF is considered to be a healing biomaterial, and presently, studies have shown its application in various disciplines of dentistry. PRF is the second generation of platelet concentrates which allows fibrin membranes to get enriched with platelets and growth factors, starting from an anticoagulant free blood harvest. PRF is similar to a fibrin network that allows cell migration and proliferation, and consequently, a more efficient cicatrization. Many growth factors, such as platelet-derived growth factor and transforming growth factor, are released from PRF. One of the major differences between PRF and PRP is the different polymerization that is responsible for the different biologic properties. PRF released autologous growth factors gradually and expressed stronger and more durable effect on proliferation and differentiation, which means that PRF could stimulate the surrounding environment to a more rapid wound healing. This review aims to evaluate the effect of biologic characteristics of fibrin glues, PRP, and PRF

The Relationship between Structure of the Corticoreticular Tract and Walking Capacity in Children with Cerebral Palsy

Background: Disruption in the descending pathways may lead to gait impairments in Cerebral Palsy (CP) children. Though, the mechanisms behind walking problems have not been completely understood.Objective: We aimed to define the relationship between the structure of the corticoreticular tract (CRT) and walking capacity in children with CP.Material and Methods: This is a retrospective, observational, and cross-sectional study. Twenty-six children with CP between 4 to 15 years old participated. Also, we used existed data of healthy children aged 4 to 15 years old. CRT structure was characterized using diffusion tensor imaging (DTI). The DTI parameters extracted to quantify CRT structure included: fractional anisotropy (FA), mean (MD), axial (AD), and radial (RD) diffusivity. Balance and walking capacity was evaluated using popular clinical measures, including the Berg balance scale (BBS), Timed-Up-and-Go (TUG; balance and mobility), six-minute walk test (6 MWT; gait endurance), and 10-meter walk Test (10 MWT; gait speed).Results: There are significant differences between MD, AD, and RD in CP and healthy groups. Brain injury leads to various patterns of the CRT structure in children with CP. In the CP group with abnormal CRT patterns, DTI parameters of the more affected CRT are significantly correlated with walking balance, speed, and endurance measures. Conclusion: Considering the high inter-subject variability, the variability of CRT patterns is vital for determining the nature of changes in CRT structure, their relationship with gait impairment, and understanding the underlying mechanisms of movement disorders. This information is also important for the development or prescription of an effective rehabilitation target for individualizing treatment

Board of Director Characteristics and CEO compensation: Empirical Evidence from Iran

This study aims to investigate the relationship between Board of Director characteristics and CEO compensation. This is semi-empirical study and statistical sample of research was based on 95 companies listed on the Tehran stock exchange from 2010 to 2014. Variables examined include the ratio of non-executive board members, CEO duality, ownership of institutional shareholders and managerial ownership as independent variables. Factors influencing CEO compensation were considered and the relationship between these variables was studied using multivariate regression. The findings indicate that there is a negative relationship between CEO compensation and managerial ownership. There is also a significant positive relationship between CEO compensation and CEO duality. However, there was no evidence for a significant relationship between ratios of non-executive board members and CEO compensation

The effect of novel probiotic on performance and serum concentrations of cholesterol and triglyceride in broiler chickens

In this experiment, effects of two phosphate solublizing bacteria as a novel probiotic on performance factors and serum concentrations of cholesterol and triglyceride were investigated. The experiment included 320 Ross broilers from 1 to 49 days of age. Birds were randomly allocated to 4 treatments, with 4 replicates of 20 birds. Treatments include (1) basal diet with no additives (control); (2) basal diet + 0.25% probiotic in starter, grower and finisher; (3) basal diet + 0.25% probiotic in grower and finisher; and (4) basal diet + 0.25% probiotic in finisher. The results obtained in this experiment showed that the probiotic significantly increased body weight gain and improved feed conversion ratio (P < 0.05). However, the probiotic supplementation did not affect feed intake between treatments (P > 0.05). In addition, results showed that probiotic caused significantly decrease on the serum cholesterol and triglyceride (P < 0.05).Key words: Probiotic, phosphate solublizing bacteria, cholesterol, broiler

Catalytic mechanism of human glyoxalase i studied by quantum-mechanical cluster calculations

Density functional theory has been used to study the mechanism and stereospecificity of the catalytic reaction of human glyoxalase I. We used the quantum mechanical cluster method to model the enzyme active site. Glyoxalase I accepts both enantiomers of the hemithioacetal between methylglyoxal and glutathione and converts them to the S-D enantiomer of lactoylglutathione. We have compared several previously suggested or alternative reaction mechanisms for both substrates on an equal footing. The results show that the coordination shell of the Zn ion in the optimized geometries is more symmetric than in some inhibitor crystal structures, which we assign to differences in the electronic structure and the protonation states of the substrate. The symmetry of the active site model indicates that the enzyme can use the same reaction mechanism for the S and the R enantiomers of the substrate, but with exchanged roles of the two active-site glutamate residues. However, the calculations show some asymmetry (0-4 kcal mol-1 differences in reaction energies and activation barriers), caused by the different coordination states of the glutamate residues in the starting crystal structure. Our results indicate that the only possibility for the stereospecificity of glyoxalase I is differences in the electrostatic surroundings and flexibility of the glutamate residues in the active site owing to their neighboring residues in the protein

Two local minima for structures of [4Fe–4S] clusters obtained with density functional theory methods

Abstract [4Fe–4S] clusters are essential cofactors in many proteins involved in biological redox-active processes. Density functional theory (DFT) methods are widely used to study these clusters. Previous investigations have indicated that there exist two local minima for these clusters in proteins. We perform a detailed study of these minima in five proteins and two oxidation states, using combined quantum mechanical and molecular mechanical (QM/MM) methods. We show that one local minimum (L state) has longer Fe–Fe distances than the other (S state), and that the L state is more stable for all cases studied. We also show that some DFT methods may only obtain the L state, while others may obtain both states. Our work provides new insights into the structural diversity and stability of [4Fe–4S] clusters in proteins, and highlights the importance of reliable DFT methods and geometry optimization. We recommend r2SCAN for optimizing [4Fe-4S] clusters in proteins, which gives the most accurate structures for the five proteins studied