In recent years, the temperature dependence of primary kinetic isotope effects (KIE) has been used as indicator for physical nature enzyme-catalyzed H-transfer reactions. An interactive study where experimental data and calculations examine same chemical transformation is a critical means to interpret more properly KIEs. Here, rate-limiting step thymidylate synthase-catalyzed reaction studied by hybrid quantum mechanics/molecular mechanics (QM/MM) simulations in theoretical framework...

Cysteine proteases of the papain family are involved in many diseases, making them attractive targets for developing drugs. In this paper, different catalytic mechanisms cruzain cysteine protease have been studied on basis molecular dynamics simulations within hybrid quantum mechanics/molecular mechanics potentials. The obtained free energy surfaces allowed characterizing every single step along mechanisms. results confirm that full process can be divided into an acylation and a deacylation...

Cruzain is a primary cysteine protease expressed by the protozoan parasite Trypanosoma cruzi during Chagas disease infection, and thus, development of inhibitors this protein promising target for designing an effective therapy against disease. In paper, mechanism inhibition cruzain two different irreversible peptidyl halomethyl ketones (PHK) has been studied means hybrid quantum mechanics/molecular mechanics-molecular dynamics (MD) simulations to obtain complete representation possible free...

In some enzymatic systems large conformational changes are coupled to the chemical step, in such a way that dispersion of rate constants can be observed single-molecule experiments, each corresponding reaction from different reactant valley. Under this perspective here we present computational study pyruvate lactate transformation catalyzed by dehydrogenase. The consists hydride transfer and proton seem take place concertedly. degree asynchronicity energy barrier depend on particular...

The cleavage of covalent C-H bonds is one the most energetically demanding, yet biologically essential, chemical transformations. Two bond cleavages are involved in reaction catalyzed by thymidylate synthase (TSase), which provides sole de novo source (i.e., DNA base T) for organisms. Our QM/MM free energy calculations show that → O proton transfer has three transition states similar but structurally diverse. These characteristics different from our previous calculation results on C hydride...

Abstract In Nature, the family of copper monooxygenases comprised peptidylglycine α‐hydroxylating monooxygenase (PHM), dopamine β‐monooxygenase (DβM), and tyramine (TβM) is known to perform dioxygen‐dependent hydroxylation aliphatic CH bonds by using two uncoupled metal sites. spite many investigations, including biochemical, chemical, computational, details bond oxygenation mechanism remain elusive. Herein we report an investigation PHM hybrid quantum/classical potentials (i.e., QM/MM)....

Because of the increasing resistance malaria parasites to antimalarial drugs, lack highly effective vaccines, and an inadequate control mosquito vectors, problem is growing, especially in developing world. New approaches drug development are consequently required. One proteases involved degradation human hemoglobin named falcipain-2 (FP2), which has emerged as a promising target for novel drugs. However, very little known about inhibition FP2. In this paper, FP2 by epoxysuccinate E64 been...

Cysteine proteases are the most abundant in parasitic protozoa and they essential enzymes to life cycle of several them, thus becoming attractive therapeutic targets for development new inhibitors. In this paper, a computational study inhibition mechanism cysteine protease by dipeptidyl-2,3-epoxyketone Cbz-Phe-Hph-(S), recently proposed inhibitor, has been carried out means molecular dynamics (MD) simulations with hybrid QM/MM potentials. The computed free energy surfaces peptidyl...

Salicylate synthase from Mycobacterium tuberculosis, MbtI, is a highly promiscuous Mg2+ dependent enzyme with up to four distinct activities detected in vitro: isochorismate (IS), pyruvate lyase (IPL), salicylate (SS) and chorismate mutase (CM). In this paper, Molecular Dynamic (MD) simulations employing hybrid quantum mechanics/molecular mechanics (QM/MM) potentials have been carried out get detailed knowledge of the IS IPL at molecular level. According our simulations, architecture MbtI...

The origin of the enzyme's powerful role in accelerating chemical reactions is one most critical and still widely discussed questions. It already accepted that enzymes impose an electrostatic field onto their substrates by adopting complex three-dimensional structures; therefore, preorganization electric fields inside protein active sites has been proposed as a crucial contributor to catalytic mechanisms rate constant enhancement. In this work, we focus on three catalytically β-subunits 20S...

We present a QM/MM study of the potential energy surface pyruvate to lactate transformation catalyzed by L-lactate dehydrogenase. The involves hydride and proton transfer which are followed means corresponding antisymmetric combination distances from hydrogen atom donor acceptor atoms. To discriminate among possible reaction mechanisms we have considered different improvements AM1/MM description: reoptimization van der Waals parameters inclusion corrections QM associated with both...

The catalytic mechanism of dihydrofolate reductase (DHFR) requires the addition both a proton and hydride ion. In Escherichia coli (ecDHFR) Asp27 is considered as only group in active site capable providing for reduction N5−C6 bond, although it not clear enough if takes place directly or through series water molecules. this paper we present theoretical study protonation N5 hydrofolate, prior step transfer reductase. Hybrid quantum-mechanical/molecular-mechanical (QM/MM) calculations...

We have studied the alkaline hydrolysis of p-nitrophenylmethylphosphate (p-NPmP) in aqueous solution by means polarizable continuum models and hybrid quantum-mechanical/molecular-mechanical (QM/MM) methods. The theoretical predictions kinetic isotope effects (KIEs) are very good agreement with experimental data, confirming a concerted asynchronous molecular mechanism. In addition, comparison high level DFT theory semiempirical AM1/d Hamiltonian has allowed checking reliability later to be...

We have studied the dependence of chemical reaction mechanism L-lactate dehydrogenase (LDH) on protonation state titratable residues and level quantum mechanical (QM) description by means hybrid quantum-mechanical/molecular-mechanical (QM/MM) methods; this methodology has allowed clarification timing hydride transfer proton components that hitherto had not been possible to definitively.

Abstract We are presenting a theoretical study of the hydrolysis β‐lactam antibiotic in gas phase and aqueous solution by means hybrid quantum mechanics/molecular mechanics potentials. After exploring potential energy surfaces at semiempirical density functional theory (DFT) level, potentials mean force have been computed for reaction with PM3/TIP3P calculations corrections B3LYP M06‐2X functionals. Inclusion full molecule antibiotic, Cefotaxime, molecular model has demonstrated to be...

The objective of this study was to examine the relationship between different sleep parameters and energy macronutrient intake in school-aged children. A total 203 children 6 9 years age participated cross-sectional study. Anthropometric measurements were taken first. Diet assessed with 3-day food logs measured a questionnaire on quality wrist actigraph worn for at least 7 days. decrease 165.45 kcal observed per each additional hour during week (β (95% CI) = -165.45 (-274.01, -56.88); p...

20S proteasome is a main player in the protein degradation pathway cytosol, thus intervening multiple pivotal cellular processes. Over years has emerged as crucial target for treatment of many diseases such neurodegenerative diseases, cancer, autoimmune developmental disorders, cystic fibrosis, diabetes, cardiac atherosclerosis, and aging. In this work, mechanism covalent inhibition with bisbenzyl-protected homobelactosin C (hBelC) was explored using quantum mechanics/molecular mechanics...

Molecular simulations based on the use of hybrid quantum mechanics/molecular mechanics methods are able to provide detailed information about complex enzymatic reactions and consequences specific mutations activity enzyme. In this work, reduction pyruvate lactate catalysed by wild-type Asp168Ala mutant dehydrogenase (LDH) has been studied means using a very flexible molecular model consisting full tetramer enzyme, together with cofactor NADH, substrate solvent water molecules. Our results...