Jeremy Kua

Thermodynamics and kinetics of methylglyoxal dimer formation: a computational study.

Density functional theory (B3LYP//6-311+G*) calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, are applied to study the hydration of methylglyoxal and the subsequent formation of dimeric species in solution. Our calculations show that, unlike glyoxal, fully hydrated species are not thermodynamically favored over their less hydrated counterparts, nor are dioxolane ring species the thermodynamic sink, which is in agreement with experimental data. Instead, we find that aldol condensations are the most favored oligomerization reactions for methylglyoxal. These results differ from those of glyoxal, which, lacking the methyl group, cannot access the enol structure leading to aldol condensation. For methylglyoxal, the product from nucleophilic attack at the aldehyde rather than the ketone was favored. Our results help explain some of the observed differences between methylglyoxal and glyoxal, in particular the different array of oligomers formed.

Molecular docking of balanol to dynamics snapshots of protein kinase A

Even if the structure of a receptor has been determined experimentally, it may not be a conformation to which a ligand would bind when induced fit effects are significant. Molecular docking using such a receptor structure may thus fail to recognize a ligand to which the receptor can bind with reasonable affinity. Here, we examine one way to alleviate this problem by using an ensemble of receptor conformations generated from a molecular dynamics simulation for molecular docking. Two molecular dynamics simulations were conducted to generate snapshots for protein kinase A: one with the ligand bound, the other without. The ligand, balanol, was then docked to conformations of the receptors presented by these trajectories. The Lamarckian genetic algorithm in Autodock [Goodsell et al. J Mol Recognit 1996;9(1):1–5 ; Morris et al. J Comput Chem 1998;19(14):1639–1662 ] was used in the docking. Three ligand models were used: rigid, flexible, and flexible with torsional potentials. When the snapshots were taken from the molecular dynamics simulation of the protein–ligand complex, the correct docking structure could be recovered easily by the docking algorithm in all cases. This was an easier case for challenging the docking algorithm because, by using the structure of the protein in a protein–ligand complex, one essentially assumed that the protein already had a pocket to which the ligand can fit well. However, when the snapshots were taken from the ligand‐free protein simulation, which is more useful for a practical application when the structure of the protein–ligand complex is not known, several clusters of structures were found. Of the 10 docking runs for each snapshot, at least one structure was close to the correctly docked structure when the flexible‐ligand models were used. We found that a useful way to identify the correctly docked structure was to locate the structure that appeared most frequently as the lowest energy structure in the docking experiments to different snapshots. Proteins 2005.

Thermodynamics and Kinetics of Imidazole Formation from Glyoxal, Methylamine, and Formaldehyde: A Computational Study

Density functional theory calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, are applied to study the mechanism of experimentally observed imidazole formation from the reaction of glyoxal and methylamine in solution. Our calculations suggest that a diimine species is an important intermediate in the reaction. Under acidic conditions, we find that the diimine acts as a nucleophile in attacking the carbonyl group of either formaldehyde or glyoxal to first generate an acyclic enol intermediate, which then goes on to close the ring and form imidazoles. Our results confirm that formaldehyde and, by extension, other small aldehydes are likely to be incorporated into imidazole ions in the presence of glyoxal and primary amines in clouds and aqueous aerosol. This is a new mechanism of aerosol formation by formaldehyde, the most abundant aldehyde in the atmosphere. The amount of aerosol formed will depend on the amounts of glyoxal and amines present.

Strategies for Multiscale Modeling and Simulation of Organic Materials: Polymers and Biopolymers

Abstract Advances in theory and methods are making it practical to consider fully first principles (de novo) predictions of structures, properties and processes for organic materials. However, despite the progress there remains an enormous challenge in bridging the vast range of distances and time scales between de novo atomistic simulations and the quantitative continuum models for the macroscopic systems essential in industrial design and operations. Recent advances relevant to such developments include: quantum chemistry including continuum solvation and force field embedding, de novo force fields to describe phase transitions, molecular dynamics (MD) including continuum solvent, non equilibrium MD for rheology and thermal conductivity and mesoscale simulations. To provide some flavor for the opportunities we will illustrate some of the progress and challenges by summarizing some recent developments in methods and their applications to polymers and biopolymers. Four different topics will be covered: (1) hierarchical modeling approach applied to modeling olfactory receptors, (2) stabilization of leucine zipper coils by introduction of trifluoroleucine, (3) modeling response of polymers sensors for electronic nose, and (4) diffusion of gases in amorphous polymers.

Studying the roles of W86, E202, and Y337 in binding of acetylcholine to acetylcholinesterase using a combined molecular dynamics and multiple docking approach

A combined molecular dynamics simulation and multiple ligand docking approach is applied to study the roles of the anionic subsite residues (W86, E202, Y337) in the binding of acetylcholine (ACh) to acetylcholinesterase (AChE). We find that E202 stabilizes docking of ACh via electrostatic interactions. However, we find no significant electrostatic contribution from the aromatic residues. Docking energies of ACh to mutant AChE show a more pronounced effect because of size/shape complementarity. Mutating to smaller residues results in poorer binding, both in terms of docking energy and statistical docking probability. Besides separating out electrostatics by turning off the partial charges from each residue and comparing it with the native, the mutations in this study are W86F, W86A, E202D, E202Q, E202A, Y337F, and Y337A. We also find that all perturbations result in a significant reduction in binding of extended ACh in the catalytically productive orientation. This effect is primarily caused by a small shift in preferred position of the quaternary tail.

Direct comparisons of rates for low temperature diffusion of hydrogen and deuterium on Cu(001) from quantum mechanical calculations and scanning tunneling microscopy experiments

Recent experiments by Lauhon and Ho using scanning tunneling microscopy (STM) observed the direct hopping of H and D on Cu(001) as a function of temperature. They found nearly temperature independent tunneling for H below 60 K, but could not detect the tunneling threshold for D (it is at least 1000 times lower than for H). The availability of such direct and accurate measurements provides the opportunity for validating the level of theory required to predict the diffusion of adsorbates on surfaces. Thus, we carried out density functional theory (DFT) using the generalized gradient approximation (GGA-II) on periodic slabs. The calculated tunneling rate of 4.74×10−4 s−1 for H is in close agreement with the experimental value of 4.4×10−4 s−1. We predict 4.66×10−9 s−1 for the tunneling rate of D (one hop every 83 months!). Between 60 and 80 K, the calculated thermally activated diffusion rate of H is 1012.88 exp(−0.181 eV/kT) s−1 in close agreement with the STM value: 1012.9±0.3 exp(−0.197 eV/kT). For deuteri...

Primordial ocean chemistry and its compatibility with the RNA world.

We examine the stability of three key components needed to establish an RNA World under a range of potential conditions present on the early earth. The stability of ribose, cytosine, and the phosphodiester bond are estimated at different pH values and temperatures by extrapolating available experimental data. The conditions we have chosen range from highly acidic or alkaline hydrothermal vents, to the milder conditions in a primordial ocean at a range of atmospheric CO2 partial pressures.

Glycolaldehyde Monomer and Oligomer Equilibria in Aqueous Solution: Comparing Computational Chemistry and NMR Data

A computational protocol utilizing density functional theory calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, is applied to study the thermodynamic and kinetic energy landscape of glycolaldehyde in solution. Comparison is made to NMR measurements of dissolved glycolaldehyde, where the initial dimeric ring structure interconverts among several species before reaching equilibrium where the hydrated monomer is dominant. There is good agreement between computation and experiment for the concentrations of all species in solution at equilibrium, that is, the calculated relative free energies represent the system well. There is also relatively good agreement between the calculated activation barriers and the estimated rate constants for the hydration reaction. The computational approach also predicted that two of the trimers would have a small but appreciable equilibrium concentration (>0.005 M), and this was confirmed by NMR measurements. Our results suggest that while our computational protocol is reasonable and may be applied to quickly map the energy landscape of more complex reactions, knowledge of the caveats and potential errors in this approach need to be taken into account.

Hetero-arylboroxines: the first rational synthesis, X-ray crystallographic and computational analysis

A novel series of hetero-arylboroxines were synthesized and structurally characterized by X-ray diffraction, NMR and computational analysis. The solid-state structures of the hetero-arylboroxines represent the first report of AB(2)-type hetero-arylboroxines.

Free Energy Map for the Co-Oligomerization of Formaldehyde and Ammonia

Density functional theory calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, are applied to construct a free energy map of formaldehyde and ammonia co-oligomerization in aqueous solution at pH 7. The stepwise route to forming hexamethylenetetramine (HMTA), the one clearly identified major product in a complex mixture, involves a series of addition reactions of formaldehyde and ammonia coupled with dehydration and cyclization reactions at key steps in the pathway. The free energy map also allows us to propose the possible identity of some major peaks observed by mass spectroscopy in the reaction mixture being the result of stable species not along the pathway to HMTA, in particular those formed by intramolecular condensation of hydroxyl groups to form six-membered rings with ether linkages. Our study complements a baseline free energy map previously worked out for the self-oligomerization of formaldehyde in solution at pH 7 using the same computational protocol and published in this journal (J. Phys. Chem. A 2013, 117, 12658).