Upendra Adhikari

Substituent effects on CL···N, S···N, and P···N noncovalent bonds.

Cl, S, and P atoms have previously been shown as capable of engaging in a noncovalent bond with the N atom on another molecule. The effects of substituents B on the former atoms on the strength of this bond are examined, and it is found that the binding energy climbs in the order B = CH(3) < NH(2) < CF(3) < OH < Cl < NO(2) < F. However, there is some variability in this pattern, particularly for the NO(2) group. The A···N bonds (A = Cl, S, P) can be quite strong, amounting to as much as 10 kcal/mol. The binding energy arises from approximately equal contributions from its induction and electrostatic components, although the former becomes more dominant for the stronger bonds. The induction energy is due in large measure to the transfer of charge from the N lone pair to a B-A σ* antibonding orbital of the electron-acceptor molecule containing Cl, S, or P. These A···N bonds typically represent the lowest-energy structure on each potential energy surface, stronger than H-bonds such as NH···F, CH···N, or SH···N.

Abilities of Different Electron Donors (D) to Engage in a P∙∙∙D Noncovalent Interaction

Previous work has documented the ability of the P atom to form a direct attractive noncovalent interaction with a N atom, based in large measure on the charge transfer from the N lone pair into the σ* antibonding orbital of the P-H that is turned away from the N atom. The present work considers whether other atoms, namely, O and S, can also participate as electron donors, and in which bonding environments. Also considered are the π-systems of multiply bonded C atoms. Unlike an earlier observation that the interaction is unaffected by the nature of the electron-acceptor atom, there is strong sensitivity to the donor. The P···D binding energy diminishes in the order D = NH(3) > H(2)CO > H(2)CS > H(2)O > H(2)S, different from the patterns observed in both H and halogen bonds. The P···D interactions are comparable to, and in some cases stronger than, the analogous H-bonds formed by HOH as proton donor. The carbon π systems form surprisingly strong P···D complexes, augmented by the back-donation from the P lone pair to the C-C π* antibond, which surpass the strengths of H-bonds, even some with HF as proton donor.

Effects of Charge and Substituent on the S···N Chalcogen Bond

Neutral complexes containing a S···N chalcogen bond are compared with similar systems in which a positive charge has been added to the S-containing electron acceptor, using high-level ab initio calculations. The effects on both XS···N and XS(+)···N bonds are evaluated for a range of different substituents X = CH3, CF3, NH2, NO2, OH, Cl, and F, using NH3 as the common electron donor. The binding energy of XMeS···NH3 varies between 2.3 and 4.3 kcal/mol, with the strongest interaction occurring for X = F. The binding is strengthened by a factor of 2-10 in charged XH2S(+)···NH3 complexes, reaching a maximum of 37 kcal/mol for X = F. The binding is weakened to some degree when the H atoms are replaced by methyl groups in XMe2S(+)···NH3. The source of the interaction in the charged systems, like their neutral counterparts, is derived from a charge transfer from the N lone pair into the σ*(SX) antibonding orbital, supplemented by a strong electrostatic and smaller dispersion component. The binding is also derived from small contributions from a CH···N H-bond involving the methyl groups, which is most notable in the weaker complexes.

Conservation and functional importance of carbon-oxygen hydrogen bonding in AdoMet-dependent methyltransferases.

S-adenosylmethionine (AdoMet)-based methylation is integral to metabolism and signaling. AdoMet-dependent methyltransferases belong to multiple distinct classes and share a catalytic mechanism that arose through convergent evolution; however, fundamental determinants underlying this shared methyl transfer mechanism remain undefined. A survey of high-resolution crystal structures reveals that unconventional carbon-oxygen (CH···O) hydrogen bonds coordinate the AdoMet methyl group in different methyltransferases irrespective of their class, active site structure, or cofactor binding conformation. Corroborating these observations, quantum chemistry calculations demonstrate that these charged interactions formed by the AdoMet sulfonium cation are stronger than typical CH···O hydrogen bonds. Biochemical and structural studies using a model lysine methyltransferase and an active site mutant that abolishes CH···O hydrogen bonding to AdoMet illustrate that these interactions are important for high-affinity AdoMet binding and transition-state stabilization. Further, crystallographic and NMR dynamics experiments of the wild-type enzyme demonstrate that the CH···O hydrogen bonds constrain the motion of the AdoMet methyl group, potentially facilitating its alignment during catalysis. Collectively, the experimental findings with the model methyltransferase and structural survey imply that methyl CH···O hydrogen bonding represents a convergent evolutionary feature of AdoMet-dependent methyltransferases, mediating a universal mechanism for methyl transfer.

Magnitude and Mechanism of Charge Enhancement of CH··O Hydrogen Bonds

Quantum calculations find that neutral methylamines and thioethers form complexes, with N-methylacetamide (NMA) as proton acceptor, with binding energies of 2-5 kcal/mol. This interaction is magnified by a factor of 4-9, bringing the binding energy up to as much as 20 kcal/mol, when a CH3(+) group is added to the proton donor. Complexes prefer trifurcated arrangements, wherein three separate methyl groups donate a proton to the O acceptor. Binding energies lessen when the systems are immersed in solvents of increasing polarity, but the ionic complexes retain their favored status even in water. The binding energy is reduced when the methyl groups are replaced by longer alkyl chains. The proton acceptor prefers to associate with those CH groups that are as close as possible to the S/N center of the formal positive charge. A single linear CH··O hydrogen bond (H-bond) is less favorable than is trifurcation with three separate methyl groups. A trifurcated arrangement with three H atoms of the same methyl group is even less favorable. Various means of analysis, including NBO, SAPT, NMR, and electron density shifts, all identify the (+)CH··O interaction as a true H-bond.

Preferred Configurations of Peptide-Peptide Interactions

The natural and fundamental proclivities of interaction between a pair of peptide units are examined using high-level ab initio calculations. The NH···O H-bonded structure is found to be the most stable configuration of the N-methylacetamide (NMA) model dimer, but only slightly more so than a stacked arrangement. The H-bonded geometry is destabilized by only a small amount if the NH group is lifted out of the plane of the proton-accepting amide. This out-of-plane motion is facilitated by a stabilizing charge transfer from the CO π bond to the NH σ* antibonding orbital. The parallel and antiparallel stacked dimers are nearly equal in energy, both only slightly less stable than the NH···O H-bonded structure. Both are stabilized by a combination of CH···O H-bonding and a π→π* transfer between the two CO bonds. There are no minima on the surface that are associated with O(lp)→π*(CO) transfers, due in large part to strong electrostatic repulsion between the two O atoms, which resists an approach of a carbonyl O from above the C=O bond of the other amide.

Contributions of Various Noncovalent Bonds to the Interaction between an Amide and S-Containing Molecules

N-Methylacetamide, a model of the peptide unit in proteins, is allowed to interact with CH(3) SH, CH(3)SCH(3), and CH(3)SSCH(3) as models of S-containing amino acid residues. All of the minima are located on the ab initio potential energy surface of each heterodimer. Analysis of the forces holding each complex together identifies a variety of different attractive forces, including SH⋅⋅⋅O, NH⋅⋅⋅S, CH⋅⋅⋅O, CH⋅⋅⋅S, SH⋅⋅⋅π, and CH⋅⋅⋅π H-bonds. Other contributing noncovalent bonds involve charge transfer into σ* and π* antibonds. Whereas some of the H-bonds are strong enough that they represent the sole attractive force in several dimers, albeit not usually in the global minimum, charge-transfer-type noncovalent bonds play only a supporting role. The majority of dimers are bound by a collection of several of these attractive interactions. The SH⋅⋅⋅O and NH⋅⋅⋅S H-bonds are of comparable strength, followed by CH⋅⋅⋅O and CH⋅⋅⋅S.

Manipulating unconventional CH-based hydrogen bonding in a methyltransferase via noncanonical amino acid mutagenesis.

Recent studies have demonstrated that the active sites of S-adenosylmethionine (AdoMet)-dependent methyltransferases form strong carbon-oxygen (CH···O) hydrogen bonds with the substrates sulfonium group that are important in AdoMet binding and catalysis. To probe these interactions, we substituted the noncanonical amino acid p-aminophenylalanine (pAF) for the active site tyrosine in the lysine methyltransferase SET7/9, which forms multiple CH···O hydrogen bonds to AdoMet and is invariant in SET domain enzymes. Using quantum chemistry calculations to predict the mutations effects, coupled with biochemical and structural studies, we observed that pAF forms a strong CH···N hydrogen bond to AdoMet that is offset by an energetically unfavorable amine group rotamer within the SET7/9 active site that hinders AdoMet binding and activity. Together, these results illustrate that the invariant tyrosine in SET domain methyltransferases functions as an essential hydrogen bonding hub and cannot be readily substituted by residues bearing other hydrogen bond acceptors.

First Steps in Growth of a Polypeptide Toward β-Sheet Structure

The full conformational energy surface is examined for a molecule in which a dipeptide is attached to the same spacer group as another peptide chain, so as to model the seminal steps of β-sheet formation. This surface is compared with the geometrical preferences of the isolated dipeptide to extract the perturbations induced by interactions with the second peptide strand. These interpeptide interactions remove any tendency of the dipeptide to form a C5 ring structure, one of its two normally stable geometries. A C7 structure, the preferred conformation of the isolated dipeptide, remains as the global minimum in the full molecule. However, the stability of this structure is highly dependent upon interpeptide H-bonds with the second chain. The latter forces include not only the usual NH···O interaction, but also a pair of CH···O H-bonds. The secondary minimum is also of C7 type and likewise depends in part upon CH···O H-bonds for its stability. The latter interactions also play a part in the tertiary minimum. A two-strand β-sheet structure is not yet in evidence for this small model system, requiring additional peptide units to be added to each chain.

The Direct Oxidizing Mechanism for the Reaction of Ozone and Phenol: A DFT Study

Using DFT/6-31+G (d, p) method, the structure of phenol are gained in the global optimization and properties were theoretically studied. The atomic electric charges, activation of reaction and thermodynamics parameters are obtained. The calculation shows that benzene ring in phenol tends to have electrophonic attacking substitution reaction O3 directly and form catechol and hydroquinol. The calculation of thermodynamics properties indicate that two pathways are exothermic reactions, and the Gibbs free energies (ΔG) are always less than zero, two reactions are easily occurred spontaneously. Dynamics calculations show that there is only one transition state in each reaction; through vibrational analysis we confirm the transition state. After corrected single point energy, we find that the reaction activation energies of the two reactions are small (Ea1=4.48kcal/mol and Ea2=2.87kal/mol), indicating that ortho-position and para-position products exist simultaneously, which is in accordance with the thermodynamics calculation result.