A Computational Study of the Promiscuity of the SAM-Dependent Methyltransferase AtHTMT1.

A two-pronged computational approach was taken to study the promiscuity of the SAM+-dependent methyl transferase AtHTMT1 from thale cress with several nucleophiles (Cl-, Br-, I-, NCO-, NCS-). First, enzyme-free methyl transfer reactions were studied with M05/6-311+G(2d,p) DFT calculations and electrostatic continuum models (PCM/SMD) for various chemical environments. Second, QM/MM MD simulations with semiempirical Hamiltonians (PM7, PM6-D3, AM1, PM6-D3H4) and the AMBER 14SB force field were used to study the enzyme catalyzed reaction in silico. The combination of the DFT and MD results shows that reactant desolvation generally accelerates the reaction, but it cannot explain the selectivity of the enzyme. The critical position of H2O molecules at the reactive site favors the reaction of NCS- over Cl- and Br- in agreement with experiments, but not observed in the quantum calculations for the cytosol. The addition of selected H2O molecules to the N terminus of NCS- greatly increases its reactivity, while H2O molecules attached to Cl- slow the reaction. The partial solvation of the nucleophiles in the reactive pouch holds the key to understanding the reactivity of AtHTMT1.

Computational Evidence for Homonuclear GeIGeI Dative Bonds.

Dative bonds between identical atoms of the same formal oxidation state are formed as geometric and electronic constraints turn an otherwise lone pair into a bond. Calculations at the B3LYP/6-31+g(d,p) level supported by additional atoms in molecules (AIM) and electron localization function (ELF) analyses on selected germanium polycations are used to prove the concept. The electron density (ρ) is not equally shared between the two atoms of such a homonuclear dative bond (HDB), and the associated charge transfer results in formal charges contradicting chemical convention.

Computational Study of the Degradation of S-Adenosyl Methionine in Water.

The degradation of S-adenosyl methionine (SAM) to homoserine-γ-lactone (HSL) and methyltioadenine (MTA) in water is studied with MD simulations. The AM1 Hamiltonian is used for the quantum part and the flexible AMBER force field for the H2O molecules. The MD simulations predict the free energy barrier for the degradation reaction to be between 109 and 112 kJ mol-1 and an overall gain in free energy of -26 kJ mol-1. The high barrier and the low energy gain of this reaction can be linked to interactions among the carboxylate group of the SAM molecule and solvent H2O molecules, which are not observed on the product side. Hence, the H2O molecules effectively slow down the reaction that otherwise would be much faster.

Solvent effects on the intramolecular conversion of trimethylsulfonium chloride to dimethyl sulfide and methyl chloride.

The formation of CH3Cl from (CH3)3SCl in various solvents has been studied based on M05/6-311+G(2d,p) DFT calculations to quantify the influence of the solvent on the stability of sulfonium cations. Four different pathways (one SN1, one backside and two frontside attacks for SN2) as well as the formation of different ion pairs (tripod, seesaw, and linear) are discussed to investigate the origin of the kinetic solvent effect (KSE) and the contribution of ion pairs to the overall reaction. Ion pairs are formed only in solvents with a permittivity ε lower than 28, but the reaction proceeds via a standard SN2 mechanism with a backside attack in all solvents. The formation of ion pairs does not change the order of the rate law, but it strongly influences the KSE, which can distinguish between reactions starting from free ions and those starting from ion pairs, in contrast to standard kinetic analysis.

A computational study of the activation of allenoates by Lewis bases and the reactivity of intermediate adducts.

Several chemical properties of Lewis base-allenoate adducts (LB·allenoate), such as solvent effect, basicity, nucleophilicity and cycloaddition, are studied to provide a detailed foundation for the analysis of LB-catalyzed reactions of allenoates. The zwitterionic LB·allenoates formed between methyl allenoate and Lewis bases, such as N-heterocyclic carbenes (NHCs), phosphines, amines and aza-heterocycles, are studied at the M06-2X/6-31+G* level. The addition of the LBs to the allenoate can yield Z- or E-type adducts. The formation of the Z-type adducts is more favorable in the gas phase due to electrostatic interactions. The yield of the E-type adducts increases with the permittivity of the solvent. The lowest barriers for the addition and the most stable adducts are observed with NHCs as catalysts. It is also shown that the α-carbon atom of the allenic moiety in LB·allenoate is more nucleophilic than the γ-carbon atom. Aza-arenes, phosphines and NHCs stabilize the [3 + 2]-ylides formed by the cycloaddition of LB·allenoate to ethylene; therefore, these LBs thermodynamically support the [3 + 2] cycloadditions. The detailed analysis of [3 + 2]-, [2 + 4]-, [2 + 2]- and [2 + 2 + 2]-cycloadditions with enones/ketones shows that the amine-catalyzed reactions follow the kinetically preferred path, and that the exergonic formation of the P-ylide favors the [3 + 2] cycloaddition in the phosphine-catalyzed reaction. The thermodynamically preferred pathway is followed with NHCs whereas the high stability of NHC·allenoate adducts reduces the overall catalytic efficiency of NHCs.

A computational study: reactivity difference between phosphine- and amine-catalyzed cycloadditions of allenoates and enones.

Allenoates and enones form cyclopentenes via a phosphine-catalyzed [3 + 2] cycloaddition while the amine-catalyzed [2 + 4] cycloaddition yields dihydropyrans or pyrans. The difference between these catalysts is studied with M06-2X/6-31+G* calculations. The addition of the catalyst to the allenoate is the first step in both pathways followed by the reaction with the enone. The formation of the [3 + 2] phosphorus-ylide is exergonic, and hence, the [3 + 2] cycloaddition is kinetically favored over the [2 + 4] addition. Amines do not stabilize [3 + 2] ammonium-ylides. However, electron-withdrawing groups on the enone enable [2 + 4] cycloadditions. The strength of the electron-withdrawing group further controls the α/γ regioselectivity of the [2 + 4] cycloaddition, and the analysis of the HOMO-LUMO interactions explains why only E-dihydropyrans from the direct γ-[2 + 4] cycloaddition have been observed in experiments. The quantum calculations further reveal a new path to the α-[2 + 4] product starting with an intermediate Rauhut-Currier reaction. This new path is kinetically favored over the direct amine-catalyzed α-[2 + 4] cycloaddition.

A constrained reduced-dimensionality search algorithm to follow chemical reactions on potential energy surfaces.

A constrained reduced-dimensionality algorithm can be used to efficiently locate transition states and products in reactions involving conformational changes. The search path (SP) is constructed stepwise from linear combinations of a small set of manually chosen internal coordinates, namely the predictors. The majority of the internal coordinates, the correctors, are optimized at every step of the SP to minimize the total energy of the system so that the path becomes a minimum energy path connecting products and transition states with the reactants. Problems arise when the set of predictors needs to include weak coordinates, for example, dihedral angles, as well as strong ones such as bond distances. Two principal constraining methods for the weak coordinates are proposed to mend this situation: static and dynamic constraints. Dynamic constraints are automatically activated and revoked depending on the state of the weak coordinates among the predictors, while static ones require preset control factors and act permanently. All these methods enable the successful application (4 reactions are presented involving cyclohexane, alanine dipeptide, trimethylsulfonium chloride, and azafulvene) of the reduced dimensionality method to reactions where the reaction path covers large conformational changes in addition to the formation/breaking of chemical bonds. Dynamic constraints are found to be the most efficient method as they require neither additional information about the geometry of the transition state nor fine tuning of control parameters.

A computational study of organic polyradicals stabilized by chromium atoms.

Density functional theory has been used to investigate the properties of organic high spin molecules. The M05/cc-pVDZ calculations predict a septet ground state for the 2,3,6,7,10,11-hexahydro-1,4,5,8,9,12-hexaoxocoronene-2,3,6,7,10,11-hexayl radical (coronene-6O). The computations show further that the formation of intermolecular carbon-carbon bonds yields a singlet ground state for the dimer rather than a possible tridectet state as expected from the monomer's multiplicity. A benzene molecule placed between coronene-6O molecules leads to the desired high-spin cluster, but the overall stability of the cluster is low. A chromium atom inserted between two peripheral C(6) rings of coronene-6O yields a sandwich structure with the expected tridectet ground state and a binding energy which is 15 times larger than the corresponding tridectet dimer stabilized by a benzene molecule. The presented DFT calculations suggest that a chromium atom can effectively link organic polyradicals to larger magnetic units.

A quantum description of the proton movement in an idealized NHN+ bridge.

A series of model calculations was done to analyze the delocalization of the proton in the linking hydrogen bond of the (Dih)(2)H(+) cation (Dih: 4,5-dihydro-1H-imidazole). Standard quantum chemical calculations (B3LYP/D95+(d,p)) predict a low barrier hydrogen bond (LBHB) and thereby a delocalized proton in the NHN(+) hydrogen bridge. Explicit quantum calculations on the proton indicate that the delocalization of the proton does not provide enough energy to stabilize a permanent LBHB. Additional Born-Oppenheimer Molecular Dynamics (BOMD) simulations indicate further that the proton is localized at either side of the NHN(+) bridge and that a central proton position is the result of temporal averaging. The possibility of the proton to tunnel from one side to the other side of the NHN(+) bridge increases with the temperature as the trajectory of the (Dih)(2)H(+) cation runs through regions where the thermal excitation of Dih ring vibrations creates equal bonding opportunities for the proton on both sides of the bridge (vibrationally assisted proton tunneling). The quantum calculations for the proton in (Dih)(2)H(+) suggest further a broad peak for the 1 ← 0 transition with a maximum at 938 cm(-1) similar to that observed for LBHBs. Moreover, the asymmetric NHN(+) bridge in a thermally fluctuating environment is strong enough to create a significant peak at 1828 cm(-1) for the 2 ← 0 transition, while contributions from the 2 ← 1 are expected to be weak for the same reason.

A model study of the efficiency of the Asp-His-Ser triad.

The observation of the Asp-His-Ser triad (Asp: aspartate, His: histidine, Ser: serine) triad both in mammalian and bacterial proteases suggests a special efficiency. A series of B3LYP/D95*(d,p) calculations on various [X-H(beta)Y](-) dyads (as part of the [X-H(beta)Y-H(alpha)Ac](-) model triad, HAc: acetic acid) made from eight different anions X(-) and 15 different coupling elements H(beta)Y was done to analyze the molecular origin of this efficiency. The X(-) anion acts merely as an electron density donor independent of its chemical nature, and the evolutionary selection of Asp for the catalytic triad therefore seems to be caused by the pH of the triads environment. As the linking proton H(beta) moves from Y(-) to X(-), electron density is effectively moved from X(-) to Y(-) thereby increasing the proton affinity (PA) of the [X-HY](-) dyad, which finally leads to the deprotonization of the HAc molecule. The degree to which the position of H(alpha) controls the PA is dominantly determined by the coupling element HY. The model calculations indicate that 4-methyl-1H-imidazole (HMim) is a very efficient coupling element, which suggest that the evolutionary convergence to the Asp-His-Ser is not only controlled by the ready availability of the imidazole motive in His but also by its high efficiency.

Correlated proton motion in hydrogen bonded systems: tuning proton affinities.

The theorem of matching proton affinities (PA) has been widely used in the analysis of hydrogen bonds. However, most experimental and theoretical investigations have to cope with the problem that the variation of the PA of one partner in the hydrogen bond severely affects the properties of the interface between both molecules. The B3LYP/d95+(d,p) analysis of two hydrogen bonds coupled by a 5-methyl-1H-imidazole molecule showed that it is possible to change the PA of one partner of the hydrogen bond while maintaining the properties of the interface. This technique allowed us to correlate various properties of the hydrogen bond directly with the difference in the PAs between both partners: it is possible to tune the potential energy surface of the bonding hydrogen atom from that of an ordinary hydrogen bond (localized hydrogen atom) to that of a low barrier hydrogen bond (LBHB, delocalized hydrogen atom) just by varying the proton affinity of one partner. This correlation shows clearly that matching PAs are of lesser importance for the formation of a LBHB than the relative energy difference between the two tautomers of the hydrogen bond.

(H2O)10 and (H2O)12 on a virtual metal surface: the growth of ice.

(H2O)10 and (H2O)12 are used to investigate the growth of ice on metal surfaces with hexagonal symmetry. The model of the virtual metal surface was used to separate the electronic structure of the metal from that of the water cluster while maintaining the geometric constraints imposed by the metal surface on the water cluster. To complement the ab initio calculations on the water cluster, an additional multicenter analysis was done to analyze the hydrogen bonds within the clusters. These calculations suggested that the water bilayer structure adjacent to the virtual metal surface effectively shields the growing ice crystal from the metal surface.

Solubility of methane in water: the significance of the methane-water interaction potential.

The influence of the methane-water interaction potential on the value of the Henry constant obtained from molecular dynamics simulations was investigated. The SPC, SPC/E, MSPC/E, and TIP3P potentials were used to describe water and the OPLS-UA and TraPPE potentials for methane. Nonbonding interactions between unlike atoms were calculated both with one of four mixing rules and with our new methane-water interaction potential. The Henry constants obtained from simulations using any of the mixing rules differed significantly from the experimental ones. Good agreement between simulation and experiment was achieved with the new potential over the whole temperature range.

How harmful is the first law?

In his First Law (of thermodynamics), Clausius emphasized the equivalence of heat and work-conservation of energy was mentioned only indirectly. Today, the main emphasis is put on energy conservation, but the equivalence of heat and work has proven not only to be superfluous, but also highly destructive. Because of this emphasis, heat is no longer considered an independent entity. In the guise of the quantity Q heat acts in a strange double role-an entity equivalent to work, but also as something fundamentally different. The place formerly occupied by heat is now filled with an abstract quantity, the entropy S-a phantom without macroscopically relevant properties. By using a phenomenological approach to entropy, it can be shown that entropy S does indeed have easily comprehensible macroscopic properties. This approach can be used to simplify thermodynamic reasoning and to reduce the calculus of thermodynamics to a fraction of its usual extent.

Symmetry in basic physical laws.

Recent physical experiments suggest that chirality is not a purely chemical phenomenon, but seems to be an inherent feature of basic physical laws. A fundamental physical principle (the CPT theorem) connects asymmetry in space with the "arrow of time," and shows that such an arrow exists even on the level of mesons.