Hydrogen bonding between nucleic acid constituents and amino acid amide group

The formation of hydrogen-bonded complexes between 9-ethyladenine and acetamide in chloroform solution has been studied by infrared spectroscopy. Comparison of the mixed solution spectra with the sum of the spectra of the separate monomers in solution shows that cyclic heterodimers are formed when acetamide binds to adenine base. Information is also obtained about the atomic arrangement of these heterodimers, where acetamide is bound to adenine base predominantly through the pyrimidine ring. Hydrogen bonds of this nature have been also observed for concentrated aqueous solutions of adenosine 5′-monophosphate in the presence of acetamide using Raman spectroscopy.     

Hydrogen bonding of formo- and thioformohydroxamic acid with methanethiol and methaneselenol as amino acid side chain groups

Hydrogen (H-) bonding ability of most stable keto and enol tautomers of formo- and thioformohydroxamic acids has been investigated by optimizing their 1:1 aggregates with MeSH and MeSeH as model molecules for sulfur and selenium containing amino acid side chains. Although enol is the most stable conformer of thioformohydroxamic acid, yet the most stable aggregate in both hydroxamic acids (HAs) being formed with keto conformer suggests that H-bonding can influence specific conformational dominance. In the aggregates, HAs preferably act as H-bond donor and S/Se of MeSH and MeSeH act as H-bond acceptor. The S···H and Se···H H-bonds although disfavored by electrostatics yet are favored by significant charge transfer. H-bonding preference and strength of interaction of HAs with MeSH and MeSeH is remarkably similar but markedly different from MeOH. AIM and NBO analysis have been employed to understand the role of electron delocalization, bond polarizations, charge transfer etc. as contributors to stabilization energy.     

Potentials of mean force between ionizable amino acid side chains in water

Potentials of mean force (PMF) between all possible ionizable amino acid side chain pairs in various protonation states were calculated using explicit solvent molecular dynamics simulations with umbrella sampling and the weighted histogram analysis method. The side chains were constrained in various orientations inside a spherical cluster of 200 water molecules. Beglov and Roux's Spherical Solvent Boundary Potential was used to account for the solvent outside this sphere. This approach was first validated by calculating PMFs between monatomic ions (K(+), Na(+), Cl(-)) and comparing them to results from the literature and results obtained using Ewald summation. The strongest interaction (-4.5 kcal/mol) was found for the coaxial Arg(+).Glu(-) pair. Many like-charged side chains display a remarkable lack of repulsion, and occasionally a weak attraction. The PMFs are compared to effective energy curves obtained with common implicit solvation models, namely Generalized Born (GB), EEF1, and uniform dielectric of 80. Overall, the EEF1 curves are too attractive, whereas the GB curves in most cases match the minima of the PMF curves quite well. The uniform dielectric model, despite some fortuitous successes, is grossly inadequate.     

Synthesis of pyridazines functionalized with amino acid side chains

A simple route for the preparation of 3,4,6-substituted pyridazines is described by using Tebbe olefination of esters then Diels–Alder reaction of the resulting enol ethers with tetrazine.     

Statistically based reduced representation of amino acid side chains

Preferred conformations of amino acid side chains have been well established through statistically obtained rotamer libraries. Typically, these provide bond torsion angles allowing a side chain to be traced atom by atom. In cases where it is desirable to reduce the complexity of a protein representation or prediction, fixing all side-chain atoms may prove unwieldy. Therefore, we introduce a general parametrization to allow positions of representative atoms (in the present study, these are terminal atoms) to be predicted directly given backbone atom coordinates. Using a large, culled data set of amino acid residues from high-resolution protein crystal structures, anywhere from 1 to 7 preferred conformations were observed for each terminal atom of the non-glycine residues. Side-chain length from the backbone C(alpha) is one of the parameters determined for each conformation, which should itself be useful. Prediction of terminal atoms was then carried out for a second, nonredundant set of protein structures to validate the data set. Using four simple probabilistic approaches, the Monte Carlo style prediction of terminal atom locations given only backbone coordinates produced an average root mean-square deviation (RMSD) of approximately 3 A from the experimentally determined terminal atom positions. With prediction using conditional probabilities based on the side-chain chi(1) rotamer, this average RMSD was improved to 1.74 A. The observed terminal atom conformations therefore provide reasonable and potentially highly accurate representations of side-chain conformation, offering a viable alternative to existing all-atom rotamers for any case where reduction in protein model complexity, or in the amount of data to be handled, is desired. One application of this representation with strong potential is the prediction of charge density in proteins. This would likely be especially valuable on protein surfaces, where side chains are much less likely to be fixed in single rotamers. Prediction of ensembles of structures provides a method to determine the probability density of charge and atom location; such a prediction is demonstrated graphically.     

Ab initio study of hydrogen-bond formation between cyclic ethers and selected amino acid side chains

Binding energies for hydrogen-bonded complexes of six cyclic ethers with five hydrogen-bond donor molecules that mimic selected amino acid side chains have been calculated at the MP2/6-31G*, MP2/6-31+G*, MP2/6-311++G**(single point), and MP2/aug-cc-pvtz levels, using geometries obtained with or without counterpoise corrections throughout the geometry optimization. The calculated basis set superposition error (BSSE) amounts to 10-20% and 5-10% of the uncorrected binding energies for the neutral and ionic species, respectively, at the MP2/aug-cc-pvtz level. The authors conclude that the O...H distances in the hydrogen bonds and binding energies for the studied systems may be determined with uncertainties of up to 0.08 A and 1-2 kcal/mol, respectively, in comparison with the MP2/aug-cc-pvtz values at a reasonable computational cost by performing standard geometry optimization at the MP2/6-31+G* level. Hydrogen-bond formation energies are more negative for cyclic ethers compared to their counterparts with a C=C double bond in the ring next to the oxygen atom. The less negative hydrogen-bonding energy and the increased O...H separation have been attributed to the reduced basicity of the ether oxygen when the lone pairs can enter conjugation with the pi-electrons of the Calpha=Cbeta double bond. The present study is the first step toward the development of an affordable computational level for estimating the binding energies of natural product, fused ring ether systems to the human estrogen receptor.     

Strengths of hydrogen bonds involving phosphorylated amino acid side chains

Post-translational phosphorylation plays a key role in regulating protein function. Here, we provide a quantitative assessment of the relative strengths of hydrogen bonds involving phosphorylated amino acid side chains (pSer, pAsp) with several common donors (Arg, Lys, and backbone amide groups). We utilize multiple levels of theory, consisting of explicit solvent molecular dynamics, implicit solvent molecular mechanics, and quantum mechanics with a self-consistent reaction field treatment of solvent. Because the approximately 6 pKa of phosphate suggests that -1 and -2 charged species may coexist at physiological pH, hydrogen bonds involving both protonated and deprotonated phosphates for all donor-acceptor pairs are considered. Multiple bonding geometries for the charged-charged interactions are also considered. Arg is shown to be capable of substantially stronger salt bridges with phosphorylated side chains than Lys. A pSer hydrogen-bond acceptor tends to form more stable interactions than a pAsp acceptor. The effect of phosphate protonation state on the strengths of the hydrogen bonds is remarkably subtle, with a more pronounced effect on pAsp than on pSer.     

Ab initio study of hydrogen-bond formation between aliphatic and phenolic hydroxy groups and selected amino acid side chains

Hydrogen bonding was studied in 24 pairs of isopropyl alcohol and phenol as one partner, and water and amino-acid mimics (methanol, acetamide, neutral and protonated imidazole, protonated methylalamine, methyl-guanidium cation, and acetate anion) as the other partner. MP2/6-31+G* and MP2/aug-cc-pvtz calculations were conducted in the gas phase and in a model continuum dielectric environment with dielectric constant of 15.0. Structures were optimized in the gas phase with both basis sets, and zero-point energies were calculated at the MP2/6-31+G* level. At the MP2/aug-cc-pvtz level, the BSSE values from the Boys-Bernardi counterpoise calculations amount to 10-20 and 5-10% of the uncorrected binding energies of the neutral and ionic complexes, respectively. The geometry distortion energy upon hydrogen-bond formation is up to 2 kcal/mol, with the exception of the most strongly bound complexes. The BSSE-corrected MP2/aug-cc-pvtz binding energy of -27.56 kcal/mol for the gas-phase acetate...phenol system has been classified as a short and strong hydrogen bond (SSHB). The CH3NH3+...isopropyl alcohol complex with binding energy of -22.54 kcal/mol approaches this classification. The complete basis set limit (CBS) for the binding energy was calculated for twelve and six complexes on the basis of standard and counterpoise-corrected geometry optimizations, respectively. The X...Y distances of the X-H...Y bridges differ by up to 0.03 A as calculated by the two methods, whereas the corresponding CBS energy values differ by up to 0.03 kcal/mol. Uncorrected MP2/aug-cc-pvtz hydrogen-bonding energies are more negative by up to 0.35 kcal/mol than the MP2/CBS values, and overestimate the CCSD(T)/CBS binding energies generally by up to 5% for the eight studied complexes in the gas phase. The uncorrected MP2/aug-cc-pvtz binding energies decreased (in absolute value) by 11-18 kcal/mol for the ionic species and by up to 5 kcal/mol for the neutral complexes when the electrostatic effect of a polarizable model environment was considered. The DeltaECCSD(T) - DeltaEMP2 corrections still remained close to their gas-phase values for four complexes with 0, +/-1 net charges. Good correlations (R2 = 0.918-0.958) for the in-environment MP2/aug-cc-pvtz and MP2/6-31+G* hydrogen-bonding energies facilitate the high-level prediction of these energies on the basis of relatively simple MP2/6-31+G* calculations.     

9-BBN: An amino acid protecting group for functionalization of amino acid side chains in organic solvents

9-Borabicyclononane (9-BBN) has been utilized to protect functionalized amino acids for potential chemoselective side chain manipulation. The 9-BBN group imparts organic solubility to otherwise hydrophilic molecules and is tolerant of a wide range of reaction conditions. The high degree of solubility of these molecules in THF is particularly noteworthy. It is cleaved with either aqueous HCl or by exchange with ethylenediamine in methanol. [reaction: see text]     

Role of pyridine hydrogen-bonding sites in recognition of basic amino acid side chains

A series of three, new artificial receptors for guanidinium and ammonium guests has been synthesized. All three receptors have highly preorganized clefts bearing two carboxylate groups. They differ in the number of nitrogen atoms contained in their clefts, as follows: four N atoms in receptor 3, three N atoms in 4, and two nitrogens in 5. Crystallographic studies have produced the solid-state structures of the following guanidinium complexes of each receptor: 3.2CH(3)CH(2)NHC(NH(2))(2)(+), 4.2CH(3)NHC(NH(2))(2)(+), and 5.2C(NH(2))(3)(+). The conformations of the receptor molecules in all three complexes are very similar. N-Alkylguanidinium guests are bound in the clefts of 3 and 4 in similar manners, despite the loss of one hydrogen-bond acceptor nitrogen in 4 and the possible hindrance of the cavity by a CH group. In the guanidinium complex of 5, neither guest enters the cavity containing two CH groups. Complexation studies were conducted in methanol by (1)H NMR titration for several guanidinium and ammonium guests, including derivatives of the amino acids arginine and lysine. Receptor 5 binds all such guests weakly (K(s) < 4000), while 3 binds most guests very strongly (K(s) > 100 000). Receptor 3 is selective for arginine versus lysine, while 4 binds lysine better than does 3. The results generally underscore the importance of receptor preorganization and hydrogen-bonding complementarity in the design of receptors that can serve as probes for biomolecules.     

A density functional theory study of a concerted mechanism for proton exchange between amino acid side chains and water

 A concerted mechanism for proton exchange between water and the amino acid side chains of cysteine, serine, arginine and glutamic acid has been investigated with hybrid density functional theory. The models used include, besides the amino acid side chain, a number of water molecules ranging from one to five in some cases. The modeling of the amino acids without their backbones is shown to be an excellent approximation. Long-range polarization effects were incorporated through a dielectric cavity method allowing a better comparison to existing measurements for free amino acids in water. The barriers converge rather fast with the number of water molecules for all the present amino acids and the converged values are in reasonable agreement with experiments with discrepancies in the range 2–6 kcal/mol. The dielectric effects were found to be small for all systems except cysteine, where there is a lowering of the barrier by 3–5 kcal/mol. The transition states for these concerted pathways form rings in which the separated charges can be stabilized. Received: 25 October 1999 / Accepted: 5 April 2000 / Published online: 21 June 2000     

Understanding hydrogen bonding of hydroxamic acids with some amino acid side chain model molecules

The hydrogen-bonding abilities of a few amino acid side chains have been studied through aggregation of methylamine, methanol, and acetic acid (as model molecules) with formo- and thioformo- hydroxamic acids using ab initio calculations. Forty six aggregates representing all possible H-bond interactions between these amino acid side chain groups and two most stable keto and enol tautomeric forms of both hydroxamic acids have been optimized. Although participation of conventional H-bond donors and acceptors leads to significant stabilization energies, yet C–H···O, C–H···N, S–H···O, and S–H···N etc. unconventional H-bonds also contribute to stabilize interactions in many aggregates. Strength of H-bonds of the molecules with formo- and thioformo- hydroxamic acid studied follows the order acetic acid > methylamine > methanol. A comparative study of atomic charges and orbital interactions employing NBO analysis has been carried out to explore the role of bond polarizations, charge transfer, and electron delocalizations as contributors to stabilization energy.     

Electronic properties of amino acid side chains: quantum mechanics calculation of substituent effects

Background  

Electronic properties of amino acid side chains such as inductive and field effects have not been characterized in any detail. Quantum mechanics (QM) calculations and fundamental equations that account for substituent effects may provide insight into these important properties. PM3 analysis of electron distribution and polarizability was used to derive quantitative scales that describe steric factors, inductive effects, resonance effects, and field effects of amino acid side chains.     

Enthalpic pair interaction coefficient between zwitterions of L-alpha-amino acids and urea molecule as a hydrophobicity parameter of amino acid side chains

Dissolution enthalpies of L-alpha-proline, L-alpha-tyrosine, L-alpha-tryptophan, L-alpha-histidyne, L-alpha-arginine, L-alpha-lysine, L-aspartic acid, and L-alpha-glutamic acid in aqueous solutions of urea have been measured by calorimetry at a temperature of 298.15 K. The values of dissolution enthalpy were used to determine enthalpic heterogeneous pair interaction coefficients between the zwitterions of the natural amino acids and a molecule of urea in water solution. These coefficients were interpreted in terms of the hydrophobic or hydrophilic effects of the side chains of amino acids on their interactions with a polar molecule of urea in water.     

Heuristic molecular lipophilicity potential (HMLP): lipophilicity and hydrophilicity of amino acid side chains

Heuristic molecular lipophilicity potential (HMLP) is applied in the study of lipophilicity and hydrophilicity of 20 natural amino acids side chains. The HMLP parameters, surface area S(i), lipophilic indices L(i), and hydrophilic indices H(i) of amino acid side chains are derived from lipophilicity potential L(r). The parameters are correlated with the experimental data of phase-transferring free energies of vapor-to-water, vapor-to-cyclohexane, vapor-to-octanol, cyclohexane-to-water, octanol-to-water, and cyclohexane-to-octanol through a linear free energy equation DeltaG(0)(tr,i) = b(0) + b(1)S(i) (+) + b(2)S(i) (-) + b(3)L(i) + b(4)H(i). For all above six phase-transfer free energies, the HMLP parameters of 20 amino acid side chains give good calculation results using linear free energy equation. HMLP is an ab initio quantum chemical approach and a structure-based technique. Except for atomic van der Waals radii, there are no other empirical parameters used. The HMLP has clear physical and chemical meaning and provides useful lipophilic and hydrophilic parameters for the studies of proteins and peptides.     

Radical polymerization of styrene derivatives bearing N‐free amino acid side chains,synergic effect of chirality,and hydrogen bonding for stereoselective polymerization

Radical polymerization of styrene derivatives having a series of amino acid, alanine, glycine, leucine, valine, Boc‐leucine, and Boc‐valine, in the side chain bound at the C‐terminal was conducted to regulate the stereoinduction system in the propagation step. Isotacticity increased in the polymer main chain, especially in the polymerization of monomers bearing N‐free L ‐leucyl and L ‐valyl esters in THF or DMF at 50 °C, by the synergic stereoregulation with chirality control and hydrogen bonding between the radical polymer terminal and the monomer. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Array of aromatic amino acid side chains located near the chromophore of photoactive yellow protein

The role of the array of aromatic amino acid side chains located close to the chromophore binding loop of photoactive yellow protein (PYP) was studied using the alanine-substitution mutagenesis. Phe92, Tyr94, Phe96 and Tyr98 were replaced with alanine (F92A, Y94A, F96A and Y98A, respectively), then these mutants were characterized by UV-visible absorption spectra, circular dichroism (CD) spectra, thermal stability and photocycle kinetics. Absorption maxima of F92A, Y94A, F96A and Y98A were 444, 442, 439 and 447 nm, respectively, different to wild type (WT) at 446 nm. Far-UV CD spectra of mutants other than F92A were different from WT, indicating that Tyr94, Phe96 and Tyr98 maintain the native secondary structure of PYP. Mid-point temperatures of thermal denaturation of F92A, Y94A and F96A, estimated by the CD signal at 222 nm, were 5-10 degrees C lower than WT. Time constants of the photocycle estimated by flash-induced absorbance change were 0.36 s for WT and 1.4 s for Y98A, however, 100, 30 and 3000 times slower than WT for F92A, Y94A and F96A, respectively. Tyr98 is located in the loop region, whereas Phe92, Tyr94 and Phe96 are incorporated in the beta4 strand, showing that aromatic amino acid residues in the beta-sheet regulate the absorption spectrum, thermal stability and photocycle of PYP. Aromatic rings of Phe92, Tyr94 and Phe96 lie nearly perpendicular to the aromatic ring of Phe75 or chromophore. Possible weak hydrogen bonds between the aromatic ring hydrogen and pi-electrons of these residues are discussed.     

Calculation of the free energy of solvation for neutral analogs of amino acid side chains

The ability of the GROMOS96 force field to reproduce partition constants between water and two less polar solvents (cyclohexane and chloroform) for analogs of 18 of the 20 naturally occurring amino acids has been investigated. The estimations of the solvation free energies in water, in cyclohexane solution, and chloroform solution are based on thermodynamic integration free energy calculations using molecular dynamics simulations. The calculations show that while the force field reproduces the experimental solvation free energies of nonpolar analogs with reasonable accuracy the solvation free energies of polar analogs in water are systematically overestimated (too positive). The dependence of the calculated free energies on the atomic partial charges was also studied.