Binding energies of water to lithiated valine: formation of solution-phase structure in vacuo.

Dissociation kinetics for loss of a water molecule from hydrated ions of lithiated valine, alanine ethyl ester and betaine are determined using blackbody infrared radiative dissociation at temperatures between -60 and 110 degrees C. From master equation modeling of these data, values of the threshold dissociation energy are obtained for clusters containing one through three water molecules. By comparing the values for valine with its two isomers, one a model for the nonzwitterion structure, the other a model for the zwitterion structure, information about the structure of valine in these hydrated clusters is inferred. Structures, relative energies, and water binding energies for these ions are also calculated at the B3LYP/6-31++G** level of theory. With one water molecule, both experiment and theory indicate that valine is not a zwitterion and that the lithium ion coordinates with the amino nitrogen and the carbonyl oxygen (NO coordinated) and the water molecule interacts directly with the lithium ion. With two water molecules, the zwitterion and nonzwitterion structures are nearly isoenergetic, but the experiment clearly indicates a NO-coordinated nonzwitterion structure. With three water molecules, both the experimental data and theory indicate that the lithium ion binds to the carboxylate group of valine, i.e., valine is zwitterionic with three water molecules. The agreement between the experimentally determined and calculated binding energies is good for all the clusters, with deviations of <== 0.12 eV.

Optimization of propafenone analogues as antimalarial leads.

Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

Binding energies of water to doubly hydrated cationized glutamine and structural analogues in the gas phase.

The modes of metal-ion and water binding in doubly hydrated complexes of lithiated and sodiated glutamine (Gln) are probed using blackbody infrared radiative dissociation experiments and density functional theory calculations. Threshold dissociation energies, E0, for loss of a water molecule from these complexes are obtained from master-equation modeling of these data. The values of E0 are 36 +/- 1 and 38 +/- 2 kJ/mol for the lithiated and sodiated glutamine complexes, respectively, and are consistent with calculated water binding energies for the nonzwitterionic form of these complexes. Calculated water binding energies for the zwitterionic forms of these complexes are significantly higher. In contrast, calculations indicate that the zwitterionic form of Gln in these complexes is more stable than the nonzwitterionic form by 8 and 15 kJ/mol when lithiated and sodiated, respectively. Doubly hydrated lithiated and sodiated complexes of asparagine methyl ester (AsnOMe), asparagine ethyl ester (AsnOEt), and glutamine methyl ester (GlnOMe) were also studied for comparison to Gln. Although these clusters lack the acidic group of Gln and therefore have different water coordination behavior, these results further support the conclusion that Gln is nonzwitterionic in these clusters. Surprisingly, the complexes containing sodium are more stable than those containing lithium, a result that is attributed to subtle differences in how these two metal ions bind to the amino acid esters in these complexes.

Structures of lithiated lysine and structural analogues in the gas phase: effects of water and proton affinity on zwitterionic stability.

The structures of lithiated lysine, ornithine, and related molecules, both with and without a water molecule, are investigated using both density functional theory and blackbody infrared radiative dissociation experiments. The lowest-energy structure of lithiated lysine without a water molecule is nonzwitterionic; the metal ion interacts with both nitrogen atoms and the carbonyl oxygen. Structures in which lysine is zwitterionic are higher in energy by more than 29 kJ/mol. In contrast, the singly hydrated clusters with the zwitterionic and nonzwitterionic forms of lysine are more similar in energy, with the nonzwitterionic form more stable by only approximately 7 kJ/mol. Thus, a single water molecule can substantially stabilize the zwitterionic form of an amino acid. Analogous molecules that have methyl groups attached to either the N-terminus (NMeLys) or the side-chain amine (Lys(Me)) have proton affinities greater than that of lysine. In the lithiated clusters with a water molecule attached, the zwitterionic forms of NMeLys and Lys(Me) are calculated to be approximately 4 and approximately 11 kJ/mol more stable than the nonzwitterionic forms, respectively. Calculations of the potential-energy pathway for interconversion between the different forms of lysine in the lithiated complex indicate multiple stable intermediates with an overall barrier height of approximately 83 kJ/mol between the lowest-energy nonzwitterionic form and the most accessible zwitterionic form. Experimentally determined binding energies of water are similar for all these complexes and range from 57 to 64 kJ/mol. These results suggest that loss of a water molecule from the lysine complexes is both energetically and entropically favored compared to interconversion between the nonzwitterionic and zwitterionic structures. Comparisons to calculated binding energies of water to the various structures show that the experimental results are most consistent with the nonzwitterionic forms.

Structures of cationized proline analogues: evidence for the zwitterionic form.

The structures of lithiated and sodiated alpha-methyl-proline (alpha-Me-Pro) and structural isomers, both with and without a water molecule, are investigated using blackbody infrared radiative dissociation (BIRD) and density functional theory. From the BIRD kinetic data measured as a function of temperature, combined with master equation modeling of these data, threshold dissociation energies for the loss of a water molecule from these clusters are obtained. These energies are 77.5 +/- 0.5 and 53 +/- 1 kJ/mol for lithiated and sodiated alpha-Me-Pro, respectively. For the nonzwitterionic isomer, proline methyl ester, these values are 3.0-4.5 kJ/mol higher. These results provide compelling experimental evidence that alpha-Me-Pro is zwitterionic in these clusters. Theory at the temperature corrected B3LYP/6-311++G**//B3LYP/6-31++G** level indicates that the salt-bridge or zwitterionic forms of lithiated and sodiated alpha-Me-Pro are between 17 and 23 kJ/mol lower in energy than the nonzwitterionic or charge-solvated forms and that attachment of a single water molecule does not significantly change the structure or the relative energies of these clusters. The proton affinity of proline is 8 kJ/mol higher than that of alpha-Me-Pro, indicating that lithiated and sodiated singly hydrated proline should also be zwitterionic.

Structures and hydration enthalpies of cationized glutamine and structural analogues in the gas phase.

The structures of lithiated and sodiated glutamine, both with and without a water molecule, are investigated using experiment and theory. Loss of water from these complexes and from lithiated and sodiated complexes of asparagine methyl ester, asparagine ethyl ester, and glutamine methyl ester is probed with blackbody infrared radiative dissociation experiments performed over a wide temperature range. Threshold dissociation energies, E(o), for loss of a water molecule from these complexes are obtained from master equation modeling of these data. The values of E(o) are 63 +/- 1 and 53 +/- 1 kJ/mol for the lithiated and sodiated glutamine complexes, respectively. These values are similar to those for the nonzwitterionic model complexes and are in excellent agreement with calculated values. In contrast, water binding to the zwitterionic form is calculated to be significantly higher. These results indicate that glutamine in these lithiated and sodiated complexes with a water molecule are nonzwitterionic. Complexes with the asparagine side chain have slightly higher E(o) values than those with the glutamine side chain, a result consistent with more effective solvation of the metal ion due to the slightly longer side chain of glutamine. Calculations indicate that lithiated and sodiated glutamine are nonzwitterionic, with the metal ion interacting with the amine nitrogen and carbonyl oxygen from the amino acid backbone and the amide oxygen of the side chain. Addition of a water molecule does not affect the lowest-energy structure of lithiated glutamine, whereas, for sodiated glutamine, the lowest-energy zwitterionic and nonzwitterionic structures are essentially isoenergetic.

Binding energies of water to sodiated valine and structural isomers in the gas phase: the effect of proton affinity on zwitterion stability.

The structures of valine (Val) and methylaminoisobutyric acid (Maiba) bound to a sodium ion, both with and without a water molecule, are investigated using both theory and experiment. Calculations indicate that, without water, sodiated Val forms a charge-solvated structure in which the sodium ion coordinates to the nitrogen and the carbonyl oxygen (NO-coordination), whereas Maiba forms a salt-bridge structure in which the sodium ion coordinates to both carboxylate oxygens (OO-coordination). The addition of a single water molecule does not significantly affect the relative energies or structures of the charge-solvated and salt-bridge forms of either cluster, although in Maiba the mode of sodium ion binding is changed slightly by the water molecule. The preference of Maiba to adopt a zwitterionic form in these complexes is consistent with its higher proton affinity. Experimentally, the rates of water evaporation from clusters of Val.Na(+)(H(2)O) and Maiba.Na(+)(H(2)O) are measured using blackbody infrared radiative dissociation (BIRD). The dissociation rates from the Val and Maiba complexes are compared to water evaporation rates from model complexes of known structure over a wide range of temperatures. Master equation modeling of the BIRD kinetic data yields a threshold dissociation energy for the loss of water from sodiated valine of 15.9 +/- 0.2 kcal/mol and an energy of 15.1 +/- 0.3 kcal/mol for the loss of water from sodiated Maiba. The threshold dissociation energy of water for Val.Na(+)(H(2)O) is the same as that for the charge-solvated model isomers, while the salt-bridge model complex has the same water threshold dissociation energy as Maiba.Na(+)(H(2)O). These results indicate that the threshold dissociation energy for loss of a water molecule from these salt-bridge complexes is approximately 1 kcal/mol less than that for loss of water from the charge-solvated complexes.