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Orlando Acevedo

Publications and source records attributed to Orlando Acevedo.

10 recordsLinked to original sources
PubMed2006

Elucidation of hydrolysis mechanisms for fatty acid amide hydrolase and its Lys142Ala variant via QM/MM simulations.

Fatty acid amide hydrolase (FAAH) is a serine hydrolase that degrades anandamide, an endocannabinoid, and oleamide, a sleep-inducing lipid, and has potential applications as a therapeutic target for neurological disorders. Remarkably, FAAH hydrolyzes amides and esters with similar rates; however, the normal preference for esters reemerges when Lys142 is mutated to alanine. To elucidate the hydrolysis mechanisms and the causes behind this variation of selectivity, mixed quantum and molecular mechanics (QM/MM) calculations were carried out to obtain free-energy profiles for alternative mechanisms for the enzymatic hydrolyses. The methodology features free-energy perturbation calculations in Monte Carlo simulations with PDDG/PM3 as the QM method. For wild-type FAAH, the results support a mechanism, which features proton transfer from Ser217 to Lys142, simultaneous proton transfer from Ser241 to Ser217, and attack of Ser241 on the substrate's carbonyl carbon to yield a tetrahedral intermediate, which subsequently undergoes elimination with simultaneous protonation of the leaving group by a Lys142-Ser217 proton shuttle. For the Lys142Ala mutant, a striking multistep sequence is proposed with simultaneous proton transfer from Ser241 to Ser217, attack of Ser241 on the carbonyl carbon of the substrate, and elimination of the leaving group and its protonation by Ser217. Support comes from the free-energy results, which well reproduce the observation that the Lys142Ala mutation in FAAH decreases the rate of hydrolysis for oleamide significantly more than for methyl oleate.

Alanine↗
PubMed2006

Medium effects on the decarboxylation of a biotin model in pure and mixed solvents from QM/MM simulations.

The decarboxylation of imidazolidin-2-one-1-carboxylate anion 2 has been investigated via combined quantum and statistical mechanics methodology. Monte Carlo statistical mechanics simulations utilizing free-energy perturbation theory and PDDG/PM3 for the QM method yielded free-energy profiles for the reaction in water, methanol, acetonitrile, and mixed solvents. The results for free energies of activation are uniformly in close accord with experimental data and reflect large rate accelerations in progressing from protic to dipolar aprotic media. Structural and energetic analyses confirm that the rate retardation in protic solvents comes from loss of hydrogen bonding in progressing from the carboxylate anion 2 to the more charge-delocalized transition state (TS). The structure of the TS is found to be significantly affected by the reaction medium; it occurs at a 0.2-A shorter C-N separation in protic solvents than in acetonitrile. Characterization of the hydrogen bonding for 2 and the TS also provided insights for design of decarboxylase catalysts, namely, it is desirable to have three hydrogen-bond donating groups positioned to interact with the ureido oxygen along with two hydrogen-bond donors positioned to interact with the ureido nitrogen of the breaking C-N bond.

Acetonitriles↗
PubMed2006

Cope elimination: elucidation of solvent effects from QM/MM simulations.

The Cope elimination reactions for threo- and erythro-N,N-dimethyl-3-phenyl-2-butylamine oxide have been investigated using QM/MM calculations in water, THF, and DMSO. The aprotic solvents provide up to million-fold rate accelerations. The effects of solvation on the reactants, transition structures, and rates of reaction are elucidated here using two-dimensional potentials of mean force (PMF) derived from free-energy perturbation calculations in Monte Carlo simulations (MC/FEP). The resultant free energies of activation in solution are in close agreement with experiment. Ab initio calculations at the MP2/6-311+G-(2d,p) level using the PCM continuum solvent model were also carried out; however, only the QM/MM methodology was able to reproduce the large rate increases in proceeding from water to the dipolar aprotic solvents. Solute-solvent interaction energies and radial distribution functions are also analyzed and show that poorer solvation of the reactant in the aprotic solvents is primarily responsible for the observed rate enhancements. It is found that the amine oxide oxygen is the acceptor of three hydrogen bonds from water molecules for the reactant but only one to two weaker ones at the transition state. The overall quantitative success of the computations supports the present QM/MM/MC approach, featuring PDDG/PM3 as the QM method.

Alkenes↗
PubMed2005

Influence of inter- and intramolecular hydrogen bonding on kemp decarboxylations from QM/MM simulations.

The Kemp decarboxylation reaction for benzisoxazole-3-carboxylic acid derivatives has been investigated using QM/MM calculations in protic and dipolar aprotic solvents. Aprotic solvents have been shown to accelerate the rates of reaction by 7-8 orders of magnitude over water; however, the inclusion of an internal hydrogen bond effectively inhibits the reaction with near solvent independence. The effects of solvation and intramolecular hydrogen bonding on the reactants, transition structures, and the rate of reaction are elucidated using two-dimensional potentials of mean force (PMF) derived from free energy perturbation calculations in Monte Carlo simulations (MC/FEP). Free energies of activation in six solvents have been computed to be in close agreement with experiment. Solute-solvent interaction energies show that poorer solvation of the reactant anion in the dipolar aprotic solvents is primarily responsible for the observed rate enhancements over protic media. In addition, a discrepancy for the experimental rate in chloroform has been studied in detail with the conclusion that ion-pairing between the reactant anion and tetramethylguanidinium counterion is responsible for the anomalously slow reaction rate. The overall quantitative success of the computations supports the present QM/MM/MC approach, which features PDDG/PM3 as the QM method.

Adenine↗
PubMed2005

Discovery of a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics.

Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.

Amidohydrolases↗
PubMed2004

Solvent effects and mechanism for a nucleophilic aromatic substitution from QM/MM simulations.

The nucleophilic aromatic substitution (SNAr) reaction between azide ion and 4-fluoronitrobenzene has been investigated using QM/MM and DFT/PCM calculations in protic and dipolar aprotic solvents. The effects of solvation on the transition structures, the intermediate Meisenheimer complex, and the rate of reaction are elucidated. The large rate increases in proceeding from protic to dipolar aprotic solvents are only reproduced by the QM/MM methodology.

Azides↗
PubMed2004

Density functional theory determination of an axial gateway to explain the rate and endo selectivity enhancement of Diels-Alder reactions by bis(oxazoline)-Cu(II).

A novel conceptual model and unique understanding of rate and endo selectivity enhancements delivered by bis(oxazoline)-Cu(II) Lewis acid catalysts in the Diels-Alder reaction of cyclopentadiene and acrylate imide is presented. Despite previously reported kinetic and spectroscopic studies, the physical reasons for endo selectivity and rate enhancements remain poorly understood. Large-scale density functional calculations using Becke three-parameter density functional theory with the nonlocal correlation of Lee, Yang, and Parr and the 6-31G(d) basis set have been carried out for the first time to understand the geometric and energetic consequences of C(2)-substituent variation. The unique positioning of the tert-butyl C(2)-substituent with respect to the diene, referred to as the "axial gateway", maintains the electrophilicity of the catalyst by shielding the reactive metal center from nucleophilic attack. The interplay between steric and electronic factors is crucial to understanding the observed enhanced rates and endo selectivity.

Journal Article↗
PubMed2004

Enhanced sampling by multiple molecular dynamics trajectories: carbonmonoxy myoglobin 10 micros A0-->A(1-3) transition from ten 400 picosecond simulations.

The utility of multiple trajectories to extend the time scale of molecular dynamics simulations is reported for the spectroscopic A-states of carbonmonoxy myoglobin (MbCO). Experimentally, the A0-->A(1-3) transition has been observed to be 10 micros at 300 K, which is beyond the time scale of standard molecular dynamics simulations. To simulate this transition, 10 short (400 ps) and two longer time (1.2 ns) molecular dynamics trajectories, starting from five different crystallographic and solution phase structures with random initial velocities centered in a 37 A radius sphere of water, have been used to sample the native-fold of MbCO. Analysis of the ensemble of structures gathered over the cumulative 5.6 ns reveals two biomolecular motions involving the side chains of His64 and Arg45 to explain the spectroscopic states of MbCO. The 10 micros A0-->A(1-3) transition involves the motion of His64, where distance between His64 and CO is found to vary up to 8.8 +/- 1.0 A during the transition of His64 from the ligand (A(1-3)) to bulk solvent (A0). The His64 motion occurs within a single trajectory only once, however the multiple trajectories populate the spectroscopic A-states fully. Consequently, multiple independent molecular dynamics simulations have been found to extend biomolecular motion from 5 ns of total simulation to experimental phenomena on the microsecond time scale.

Animals↗
PubMed2003

The effect of solvent on a Lewis acid catalyzed Diels-Alder reaction, using computed and experimental kinetic isotope effects.

A new transition structure for the Diels-Alder reaction between isoprene and acrolein catalyzed by Et(2)AlCl is found to reconcile reported discrepancies between computed and observed secondary kinetic isotope effects (KIEs). Including the effect of solvent realigns the computed results with experiment demonstrating the importance of nonbond interactions at transition structures. Comparison of experimental and newly predicted KIE data reaffirms the ability of theory and experiment to probe the mechanism and transition structure geometry of organic reactions.

Journal Article↗