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Hybrid Schemes Based on Quantum Mechanics/Molecular Mechanics Simulations

2011

The development of characterization techniques, advanced synthesis methods, as well as molecular modeling has transformed the study of systems in a well-established research field. The current research challenges in biocatalysis and biotransformation evolve around enzyme discovery, design, and optimization. How can we find or create enzymes that catalyze important synthetic reactions, even reactions that may not exist in nature? What is the source of enzyme catalytic power? To answer these and other related questions, the standard strategies have evolved from trial-and-error methodologies based on chemical knowledge, accumulated experience, and common sense into a clearly multidisciplinary …

Carbocatalytic Oxidative Dehydrogenative Couplings of (Hetero)Aryls by Oxidized Multi‐Walled Carbon Nanotubes in Liquid Phase

2019

HNO3-oxidized carbon nanotubes catalyze oxidative dehydrogenative (ODH) carbon-carbon bond formation between electron-rich (hetero)aryls with O-2 as a terminal oxidant. The recyclable carbocatalytic method provides a convenient and an operationally easy synthetic protocol for accessing various benzofused homodimers, biaryls, triphenylenes, and related benzofused heteroaryls that are highly useful frameworks for material chemistry applications. Carbonyls/quinones are the catalytically active site of the carbocatalyst as indicated by model compounds and titration experiments. Further investigations of the reaction mechanism with a combination of experimental and DFT methods support the compet…

Catalytic Reaction Mechanism in Native and Mutant Catechol- O-methyltransferase from the Adaptive String Method and Mean Reaction Force Analysis.

2018

Catechol- O-methyltransferase is an enzyme that catalyzes the methylation reaction of dopamine by S-adenosylmethionine, increasing the reaction rate by almost 16 orders of magnitude compared to the reaction in aqueous solution. Here, we combine the recently introduced adaptive string method and the mean reaction force method, in combination with the structural and electronic descriptors to characterize the reaction mechanism. The catalytic effect of the enzyme is addressed by the comparison of the reaction in the human wild-type enzyme, in the less effective Y68A mutant, and in aqueous solution. The influence of these different environments at different stages of the chemical process and th…

Dynamics and reactivity in Thermus aquaticus N6-adenine methyltransferase.

2014

M.TaqI is a DNA methyltransferase from Thermus aquaticus that catalyzes the transfer of a methyl group from S-adenosyl-l-methionine to the N6 position of an adenine, a process described only in prokaryotes. We have used full atomistic classical molecular dynamics simulations to explore the protein–SAM–DNA ternary complex where the target adenine is flipped out into the active site. Key protein–DNA interactions established by the target adenine in the active site are described in detail. The relaxed structure was used for a combined quantum mechanics/molecular mechanics exploration of the reaction mechanism using the string method. According to our free energy calculations the reaction takes…

Theoretical study of phosphodiester hydrolysis in nucleotide pyrophosphatase/phosphodiesterase. Environmental effects on the reaction mechanism.

2010

We here present a theoretical study of the alkaline hydrolysis of methyl p-nitrophenyl phosphate (MpNPP(-)) in aqueous solution and in the active site of nucleotide pyrophosphatase/phosphodiesterase (NPP). The analysis of our simulations, carried out by means of hybrid quantum mechanics/molecular mechanics (QM/MM) methods, shows that the reaction takes place through different reaction mechanisms depending on the environment. Thus, while in aqueous solution the reaction occurs by means of an A(N)D(N) mechanism, the enzymatic process takes place through a D(N)A(N) mechanism. In the first case, we found associative transition-state (TS) structures, while in the enzyme TS structures have dissoc…

Analysis of the Decarboxylation Step in Mammalian Histidine Decarboxylase

2008

We report a hybrid quantum mechanics/molecular mechanics theoretical study on the reaction mechanism of mammalian histidine decarboxylase that allows us to obtain valuable insights on the structure of the cofactor-substrate adduct (external aldimine) in the active site of rat histidine decarboxylase. By means of molecular dynamics simulations, we traced the potential of mean force corresponding to the decarboxylation reaction of the adduct both in the active site of the enzyme and in aqueous solution. By comparing this process in both media, we have identified the key electrostatic interactions that explain the lowering of the free energy barrier in the enzyme. Our analysis also offers a va…

Catalysis in glycine N-methyltransferase: testing the electrostatic stabilization and compression hypothesis.

2006

Glycine N-methyltransferase (GNMT) is an S-adenosyl-l-methionine dependent enzyme that catalyzes glycine transformation to sarcosine. Here, we present a hybrid quantum mechanics/molecular mechanics (QM/MM) computational study of the reaction compared to the counterpart process in water. The process takes place through an SN2 mechanism in both media with a transition state in which the transferring methyl group is placed in between the donor (SAM) and the acceptor (the amine group of glycine). Comparative analysis of structural, electrostatic, and electronic characteristics of the in-solution and enzymatic transition states allows us to get a deeper insight into the origins of the enzyme's c…

Magnetic and catalytic properties of a new copper(II)–Schiff base 2D coordination polymer formed by connected helical chains

2011

Abstract A dicyanamide bridged 2D polynuclear complex of copper(II) having molecular formula [Cu2(L)(μ1,5-dca)2]n (1) has been synthesized using the Schiff base ligand N,N′-bis(salicylidene)-1,3-diaminopentane, (H2L) and sodium dicyanamide (dca). The complex presents a 2D hexagonal structure formed by 1,5-dca singly bridged helical chains connected through double 1,5-dca bridges. The chelating characteristics of the H2L Schiff base ligand results in the formation of copper(II) dimer with a double phenoxo bridge presenting a very strong antiferromagnetic coupling in the copper(II) derivative (1) (J = −510 cm−1). The dimeric asymmetric unit of 1 is very similar to the active site of the catec…

Structure–activity relationship of sphingomyelin analogs with sphingomyelinase from Bacillus cereus

2012

AbstractThe aim of this study was to examine how structural properties of different sphingomyelin (SM) analogs affected their substrate properties with sphingomyelinase (SMase) from Bacillus cereus. Using molecular docking and dynamics simulations (for SMase–SM complex), we then attempted to explain the relationship between SM structure and enzyme activity. With both micellar and monolayer substrates, 3O-methylated SM was found not to be degraded by the SMase. 2N-methylated SM was a substrate, but was degraded at about half the rate of its 2NH–SM control. PhytoPSM was readily hydrolyzed by the enzyme. PSM lacking one methyl in the phosphocholine head group was a good substrate, but PSM lack…

2020

Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the SNAr addition/elimination reactions. Such building blocks have only rarely been employed for the design of enzyme inhibitors. Herein, we demonstrate the combination of a peptidic recognition sequence with such electrophilic (het)arenes to generate highly active inhibitors of disease-relevant proteases. We further elucidate an unexpected mode of action for the trypanosomal protease rhodesain using NMR spectroscopy and mass spectrometry, enzyme kinetics and various types of simulations. After hydrolysis of an ester function in the recognition sequence of a weakly…