Mikael Peräkylä

Conformational behaviour of hydroxamic acids: ab initio and structural studies

The conformational behaviour of a series of monohydroxamic acids, p-RC6H4CONR′OH (R = Me, R′= H, Me; R = MeO, R′= H, Me; R = NO2, R′= H), and a series of dihydroxamic acids, (CH2)n(CONR′OH)2(n= 3–8, 10, R′= H and n= 7, R′= Me), in methanol, DMSO and chloroform and in the solid state has been examined using IR and NMR spectroscopy. X-Ray crystal structure determinations of p-MeC6H4CONMeOH and the monohydrate of glutarodihydroxamic acid (n= 3) together with ab initio molecular orbital calculations for several hydrated and unhydrated hydroxamic acids have been performed. Hydrogen bonding effects are shown to be important in both the solid state and solution. The cis(Z) conformation of the hydroxamate group(s)(CONHOH) is preferentially stabilized by hydrogen bonding with water molecules.

Ab initio models for receptor-ligand interactions in proteins. 4. Model assembly study of the catalytic mechanism of triosephosphate isomerase.

The catalytic mechanism of triosephosphate isomerase (TIM) was investigated with ab initio quantum mechanical calculations. Electrostatic interactions between the quantum mechanical active site and the protein and solvent environment were modeled using the finite difference Poission‐Boltzman method. The complexes of TIM with the substrate dihydroxyacetone phosphate (DHAP), five possible intermediates and the product glyceraldehyde‐3‐phosphate (GAP) were optimized in the active‐site model at the 3‐21G(*) level and energy profile for the proton abstraction from DHAP by the active‐site Glu167 was calculated at the MP2/3‐21G(*)//3‐21G(*) level. Calculated energetics of the enzyme reaction were found to be in reasonable agreement with the experimental findings. Calculations revealed that an enediol of the substrate is a probable intermediate in the enzyme reaction. It was suggested that the proton abstracted from the substrate by the active‐site glutamate goes to the carbonyl oxygen of the substrate producing enediol intermediate either directly or after it is exchanged with solvent.

Ab initio studies on organophosphorus compounds. Part 2. Monoanionic methyl methylphosphonate and methyl methylphosphinate and their sulfur analogues

The molecular properties of nine monoanionic methyl methylphosphonate and methyl methylphosphinate and their sulfur analogues have been studied by ab initio molecular orbital methods. Molecular structures, dipole moments, stability, charge distributions and torsional barriers have been reported. The effects of sulfur and oxygen substitution have been compared. Energetics for model and hydrolysis reactions have been calculated for all the compounds up to the MP2/6-31G*//6-31G* level. Phosphonate compounds with –OCH3 group were found to adopt an extended molecular backbone while –SCH3 systems preferred bent conformations. Inclusion of the correlation corrections with 6-31 G* basis set, instead of 3-21G(*) level, was found to have an effect on the calculated energetics of model reactions.

Ab initio studies on tetramethylurea and tetramethylthiourea

Abstract Ab initio molecular orbital theory at the HF and MP2 levels was applied to study the structures of tetramethylurea and tetramethylthiourea and to carry out a conformational analysis of these molecules. The calculated structural parameters are in good agreement with the experimental observations and correctly describe the deviations of the molecular geometries from the planar structures. Conformational analysis shows that the rotational motions about the Csp2-N bond are less hindered than the analogous motions in dimethylformamide and dimethylthioformamide. The methyl groups can rotate quite freely around the C-N bond in both the molecules studied here.

Ab initio studies on organophosphorus compounds. Part 1 : Monoanionic methylphosphonate and methylphosphinate and their nitrogen and sulfur analogues

The effects of sulfur and nitrogen substituents on the properties of 23 different analogues of monoanionic methylphosphonates and methylphosphinates have been investigated by an ab initio method with 3-21G(*) and 6-31G* basis sets. Conformational analyses were performed on all compounds with rotational bonds and the relative energies of conformers were studied. The effects of nitrogen and sulfur substituents were compared in terms of geometries, charge distributions and torsional barriers. In addition, the total energy changes of model reactions between the analogues were investigated. On the basis of the model reactions the most stable compounds were methylphosphonte (1), methylphosphonamidate (7) and methylphosphindithioate (20).

Ab initio models for receptor–ligand interactions in proteins. Part 1. Models for asparagine, glutamine, serine, threonine and tyrosine

Model compounds to be used in quantum mechanical receptor–ligand model calculations have been generated for the amino acids asparagine, glutamine, serine threonine and tyrosine using 3-21G and 6-31G basis sets. Interaction energy surfaces of the amino acids and candidate model compounds have been studied using methanol as a probe molecule. Acetamide is found to model asparagine and glutamine, ethanol serine and threonine, and phenol tyrosine. In the case of phenol, the splicing of basis set technique is found to be useful in further reducing the computational demands of the model compound.

Ab initio quantum mechanical gas phase and reaction field solvation study on the proton abstraction from hydroxyacetaldehyde by formate: implications for enzyme catalysis

Proton abstraction from a model carbon acid hydroxyacetaldehyde by formate has been studied using ab initio quantum mechanical calculations up to the MP4(SDQ)/6-31+G**//HF/6-31+G* level. Solvation effects are included using the polarisable continuum method. The calculated energies of several intermediates and transition states of the proton transfer reaction are found to be in reasonable agreement with the available experimental data. Calculations show that the α-carbon, which loses a proton in the reaction, retains a substantial amount of sp3 character in the transition state of the reaction. Therefore the resonance-stabilised enolate anion product, in which the α-carbon is sp2 hybridised, develops after the transition state has been passed. Inclusion of solvation energies moves the transition state to an earlier point on the reaction profile. This indicates that in the case of enzyme-catalysed reaction, in which the protein environment presumably can stabilise an enolate-like structure more efficiently than water does, the transition state would be even less enolate-like unless enzymes had other means of enhancing the reaction and making the transition state occur later. We discuss how lowering of the intrinsic reaction barrier and proton tunnelling may move the transition state of the enzyme-catalysed proton abstraction reaction to a later point on the reaction profile.

Ab initio molecular orbital study on reactivity of phenol, biphenyl, benzoate and p-hydroxybenzoate in the ˙OH addition reaction and stability of the corresponding ˙H and ˙OH cyclohexadienyl adducts

The reactivity of phenol, biphenyl, benzoate and p-hydroxybenzoate towards ˙OH addition and the relative stability of the corresponding ˙H and ˙OH cyclohexadienyl adducts have been studied using ab initio molecular orbital calculations. The compounds studied were optimized at the R(O)HF/6-31G* level. The SCRF method has been used to model solvent effects. The HOMO orbital coefficients were found to explain the observed isomeric distributions in the earlier radiolytic hydroxylation studies. The stabilization energies of the cyclohexadienyl radicals as investigated using the isodesmic reaction were found to be qualitatively different at the ROHF/6-31G*//6-31G* and ROMP2/6-31G*//6-31G* levels. The ROMP2/6-31G*//6-31G* energies revealed that the OH group stabilized most ortho and phenyl group para isomers of the cyclohexadienyl radicals.