Towards the Design of Carnitine Acyltransferase Inhibitors: Modeling the Conformational Behavior of (R)-Carnitine, (R)-Acetylcarnitine, Morpholinium rings, and 2-Oxo-1,3,6-dioxazaphosphacinium rings
Rosas-Garcia, Victor Manuel
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Full grid-search semiempirical calculations (AM1 and AM1/COSMO) on zwitterionic acetylcarnitine and carnitine, cationic acetylcholine and choline, and 3-acetoxypropanoate and 3-hydroxypropanoate in the gas phase and solution were performed. The calculated ΔHhydr for hydrolyses of acetylcarnitine to carnitine and of acetylcholine to choline show reasonable agreement with the experimental values in unbuffered solution (acetylcarnitine: -4.63 kcal/mol calc. vs. -7.43 kcal/mol exp.; acetylcholine: -3.20 kcal/mol calc. vs. -3.06 kcal/mol exp.) The results suggest that a change in the conformational populations of acetylcarnitine-carnitine upon hydrolysis maintains a nearly constant polarity, which keeps the work of desolvation of the products to a minimum. Acetylcholine-choline and acetoxypropanoate-hydroxypropanoate present a much higher work of desolvation, therefore yielding a lower free enthalpy of hydrolysis. Ab initio calculations at the RHF/6-31G* level for the carnitines and the cholines, and RHF/6-31+G for the propanoates, were done to calibrate the quality of the AM1 results for both the gas phase and in solution. The calculations in the gas phase involved full optimization of the AM1-optimized structures at the RHF/6-31G* level and RHF/6-31+G level, and single points at the MP2//RHF/6-31G* and MP2//RHF/6-31+G level to estimate correlation effects. The ab initio calculations in solution were single points on the AM1-optimized geometries and used the Tomasi solvent model. The ab initio results confirmed the qualitative reliability of the semiempirical results. The conformational behavior of several 4,4-dimethylmorpholinium rings and 4,4-dimethyl-2-oxo-1,3,6-dioxazaphosphacinium rings was examined by molecular mechanics (AMBER* and AMBER*-GB/SA). The contrast between the behavior of these heterocycles and that of the parent saturated hydrocarbon systems formed a picture of the conformational behavior of these six- and eight-membered heterocycles. Influences of factors such as shortened bond lengths, varied bond angles, presence or absence of lone pairs and substituents, and dipolar alignment are described. Morpholinium rings show increased stabilization of the twist-boat with 1,1,3,3-digem substitution, as compared to the parent cyclohexane systems. In the gas phase, the lowest chair/twist-boat energy gap is found in 2-(hydroxymethyl)-2,4,4-trimethylmorpholinium at 1.14 kcal/mol. The gap in the congruent hydrocarbon system is 5.23 kcal/mol. Differential solvation destabilizes the lowest energy twist-boat found in the gas phase, increasing the energy gap to 2.62 kcal/mol. The lowest chair/twist-boat energy gap in GB/SA water amounts to 1.45 kcal/mol, stabilized by solvation from an initial 2.13 kcal/mol in the gas phase. In the dioxazaphosphacinium rings, the preferred conformation in the gas phase is the boat-chair (BC) and the populations are conformationally heterogeneous. As substituents approach a 1,1,3,3-digem pattern, the twist-chair (TC) and twist-boat (TB) conformers are stabilized. Solvation favors boat-boat (BB) conformers, with the substituents exerting influence on the conformational preference only to stabilize the TB in two instances (cis-substituted ring and disubstituted ring). Solvation reduces the heterogeneity of the conformational populations. Modeling of phosphonate moieties required development of molecular mechanics parameters for dimethyl methylphosphonate. Dimethyl methylphosphonate conformations were calculated at the RHF/6-31+G* level. Charges were calculated by the CHelpG scheme. The results were used to generate AMBER* parameters for modeling of alkylphosphonates in the gas phase and in solution. Comparison of the results of our AMBER* parameters against three other common force fields (MM2*, MMX and UFF) showed that AMBER* reproduced better the ab initio results when comparing absolute deviations in bond lengths, bond angles and torsion angles. The modified AMBER* reproduced better than the other three force fields several X-ray geometries of alkylphosphonates.
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