Current Organic Chemistry - Volume 14, Issue 2, 2010

Long range electron transfer plays an important role in determining the three-dimensional structures adopted by extended molecular systems such as proteins, nucleic acids, organic-metal complexes, etc. The resulting attraction, which is conceivable as a chemical association of two or more molecules or of different parts of one very large molecule, provides a stabilizing force for the overall donor-acceptor complex. The nature of the attraction is not a stable chemical bond and is much weaker than covalent forces, and it is thus better characterized as a weak electron resonance. In this thematic issue of Current Organic Chemistry, eminent experts have reviewed recent advances in our understanding of these ubiquitous processes by posing more attention to the structure-function relationships. To better understand the mechanistic aspects of charge transfer reactions, the discrete state approach to electron transfer rates is not only a fully justified but an indispensable condition for it. Recent developments in the dynamics of the elementary electron transfer reactions have been reviewed by Peluso with a particular emphasis on the early electron transfer steps in bacterial photosynthetic reaction centers. There are numerous examples in the literature where there is evidence that CH••OH-bonds play important roles in the structure of small molecules and complexes. In this light, Scheiner details means of estimating the energetic contribution of a given CH••OH-bond to protein structure, and how this quantity depends upon the geometry of the interaction, and its relation to experimental measures, such as spectroscopic data. Because of insufficient experimental information on noncovalent interactions such as dispersion, hydrogen-bonding and stacking interactions between biomolecules, sophisticated quantum-chemical calculations have been shown to be an acceptable solution to this problem (Pavlov and Mitrasinovic). Novel methods for the mild and site-specific derivatization of proteins, DNA, RNA, and carbohydrates have been developed for applications such as ligand discovery, disease diagnosis, and high-throughput screening. These powerful methods owe their existence to the discovery of chemoselective reactions that enable bioconjugation under physiological conditions - a tremendous achievement of modern organic chemistry. Recent advances in bioconjugate chemistry have been reviewed in this issue (Kalia and Raines). Special emphasis has been placed on the stability of bioconjugation linkages - an important but often overlooked aspect. It is anticipated that this information will help researchers choose optimal linkages for their applications. Chemically modified biomolecules, which contain non-natural residues, have been recently introduced into a variety of biological systems in order to study the mechanism of enzyme catalysis or to design catalysts with altered substrate specificities. These new findings in combination with data from the literature have been a fundamental ground for Chirkova et al. to propose a comprehensive model for peptide bond synthesis, thus opening a new frontier in synthetic biology. In addition, the longstanding question on whether the peptide anion charge resides primarily on the ionizing nitrogen or is transferred to the carbonyl oxygen to form an imidate has been resolved using amide hydrogen exchange measurements to predict the conformational stability of proteins (Anderson et al.). Since weak interactions determine fine structures of compounds and create high functionalities of materials, Nakanishi and Hayashi have employed the quantum theory of atoms in molecules (QTAIM) to classify and evaluate weak interactions. The same QTAIM approach has been used by Mitrasinovic to propose a general methodology for extrapolating the nature of organic-metal interfacial interactions by both analyzing the topological features of the electron density at the organic/metal bond critical points (BCPs) and correlating the BCP parameters with experimental quantities such as electron affinity and ionization potential. In this way, the interfacial interactions are given physical definitions without invoking non-invariant concepts such as individual orbitals. Since experiments only detect cumulative effects of several cooperative mechanisms taking place at the metal-molecule contacts, contemporary first-principle calculations used in combination with experimental techniques have been demonstrated to lead towards a comprehensive picture of the interfacial electronic structure (Mitrasinovic). I am very grateful towards my dear colleagues, eminent scientists for their acceptance to be a part of this special issue of Current Organic Chemistry by contributing the impressive review articles on the latest relevant developments in the field. I hope that the overall effort will provide inspiration to modern organic chemists to face new interesting challenges of substantial importance with vigor.

Recent developments in the dynamics of the elementary electron transfer reactions are reviewed. Attention is mainly focused on discrete state approaches, which combine use of a few experimental data with ab initio calculation of the normal coordinates of vibration of the redox partners. Applications to the early electron transfer in bacterial photosynthetic reaction centers and future perspectives are then discussed.

It has become increasingly apparent that there are a multitude of interactions within the context of proteins where a CH group is situated near an O atom in an arrangement that would lead one to believe that there exists a H-bond between them. Indeed, there are numerous examples in the literature where there is evidence that CH••O H-bonds play important roles in the structure of small molecules and complexes. The complexity and large size of proteins, coupled with the presence of a multitude of conventional NH••OH-bonds, however, has made such unqualified documentation difficult in these macromolecules. This paper reviews work over the last few years in which quantum calculations have been applied to this problem. Calculations are used to evaluate the properties of model systems which, while smaller than full proteins, closely approximate them. Particular attention has been paid to the CαH groups of protein residues, and in common secondary structures such as α-helices and β-sheets. The calculations detail means of estimating the energetic contribution of a given CH••O H-bond, and how this quantity depends upon the geometry of the interaction, and its relation to experimental measures, such as spectroscopic data.

It has become apparent that molecular modeling is a powerful approach to examining the properties of biomolecular systems like nucleic acids and their noncovalent interactions with other substances. Theoretical studies dealing with the dynamics of such extended molecules are based on the molecular mechanics simulations exhibiting very low computational requirements without sacrificing accuracy. This advantage is balanced by a limitation that the electronic structure of the biomolecules is treated as being unaltered throughout the entire simulations. Hence, it is impossible to observe formation or break up of intra- and intermolecular interactions in order to describe the process of charge transfer. Consequently, it is indispensable to employ quantum-chemical methods, which would allow the change of electronic structure in a certain region of the biomolecular system under investigation. This article reviews advances over the last few years in which quantum-chemical wave function-based calculations have been applied to this problem.

Bioconjugation is a burgeoning field of research. Novel methods for the mild and site-specific derivatization of proteins, DNA, RNA, and carbohydrates have been developed for applications such as ligand discovery, disease diagnosis, and high-throughput screening. These powerful methods owe their existence to the discovery of chemoselective reactions that enable bioconjugation under physiological conditions-a tremendous achievement of modern organic chemistry. Here, we review recent advances in bioconjugation chemistry. Additionally, we discuss the stability of bioconjugation linkages-an important but often overlooked aspect of the field. We anticipate that this information will help investigators choose optimal linkages for their applications. Moreover, we hope that the noted limitations of existing bioconjugation methods will provide inspiration to modern organic chemists.

Chemically modified RNA nucleotides have been introduced in the past into various ribozymes in order to understand RNA folding and the mechanism of RNA catalysis. Recently the ribosome, the largest natural ribozyme known to date, has been added to the list of enzymes amenable to synthetic biology. The chemically engineered ribosomes were active in various functional assays including single-turnover peptidyl transfer reaction as well as in vitro translation assays. Solid-phase synthesis of several non-natural nucleotide analogs and their subsequent introduction into the catalytic center of the ribosome, revealed the ribose 2'-OH at position A2451 of 23S ribosomal RNA as key functional group for amide bond synthesis. By altering the chemical characteristics of the ribose at A2451 by replacing its 2'-OH with selected functional groups demonstrated that hydrogen donor capability is essential for efficient transpeptidation. These findings in combination with data that accumulated over the past years allowed to propose a comprehensive model for peptide bond synthesis in which the A2451 2'-OH directly assists in positioning one of the tRNA substrates via hydrogen-bond formation and thus supports amide bond synthesis via a proton shuttle mechanism. It is conceivable that cell-free translation systems employing rationally designed chemically engineered ribosomes can be established in the near future to produce peptides and proteins harboring unnatural amino acids.

Hydroxide-catalyzed exchange of the amide hydrogens on the protein backbone provides a highly sensitive monitor of electrostatic interactions at the aqueous interface. Much of the practical utility of these ionizations, relative to the more widely studied sidechain titrations, stems from the brief (∼10 ps) lifetime of the peptide anion intermediate which strongly limits the contribution of conformational reorganization to dielectric shielding such that electronic polarizability dominates the dielectric response of the protein. The increased sensitivity to the local electrostatic environment is manifested in the billion-fold range in exchange rates for amides that are exposed to solvent in high resolution X-ray structures. Yet to date, the exchange rates for 56 solvent exposed amides from four wellcharacterized proteins are predictable by standard continuum dielectric methods to within a factor of 7, comparing quite favorably to analogous sidechain titration analyses. Quantification of electronic interactions from short range local backbone geometry to long range formal charge effects facilitates their use in addressing questions of more general chemical interest, including the longstanding issue of whether the peptide anion charge resides primarily on the ionizing nitrogen or is transferred to the carbonyl oxygen to form an imidate ion. More fundamentally, hydrogen exchange provides experimental demonstration of the magnitude of systematic errors in the predicted electrostatic potential that can arise when dielectric shielding due to electronic polarizability is neglected in standard nonpolarizable force fields for which the electrostatic energies are optimized at the expense of accuracy in the electric field distribution.

Atoms-in-molecules (AIM) dual functional analysis is reviewed after brief introduction of AIM. Total electron energy densities (Hb(rc)) are plotted versus Laplacian of electron densities (▽2ρb(rc)) at bond critical points (BCPs). The plots draw a helical stream as a whole. For the better understanding of weak to strong interactions, polar coordinate (R, o) representation is employed for the plot of Hb(rc) versus (ħ2/8m)▽2ρb(rc). Both x- and y-axes are expressed in the common unit of energy in this treatment: Hb(rc) = Gb(rc) + Vb(rc) and (ħ2/8m)▽2ρb(rc) = Hb(rc) - Vb(rc)/2 where Gb(rc) and Vb(rc) are kinetic energy densities and potential energy densities, respectively. Interactions examined are those in van der Waals adducts, hydrogen bonded complexes, molecular complexes and hypervalent adducts through charge-transfer, and some classical covalent bonds. Data employed for the plots are calculated at BCPs for full-optimized structures and optimized structures with the fixed distances r around the full-optimized distances, ro: r = ro + wao where ao is the Bohr radius with w = ±0.1 and ±0.2. The helical stream is well described by (R, o): R is given in the energy unit and o in degree is measured from the y-axis. The ratio of Vb(rc)/Gb(rc) (= k) controls o of which acceptable range is 45.0° > o > 206.6°. Each plot for an interaction gives a curve, which supplies important information. It is expressed by op and κp: op corresponds to the tangent line measured from the ydirection and κp is the curvature of the plot at w = 0. The treatment enables us to classify, evaluate, and understand well the weak to strong interactions.

In this article, theoretical and experimental advances in the understanding of electronic processes underlying organic/metal (O/M) interface energetics are reviewed and correlated. The critical outlook comprises several key standpoints: (1) electronic basis of barrier formation at organic/metal interfaces, (2) dependence of organic/metal interface energetics on molecular conformation, (3) organic/ metal interfaces and charge injection in organic electronic devices, and (4) determination of the nature of O/M-bonded interactions using the electron density distribution. It is shown that, even in the case of weak interactions, the conformation of an organic molecule can be substantially changed upon adsorption on a metal surface, thus influencing the detailed understanding of organic/metal interfaces. Since interface energetics is essentially associated with a subtle balance amongst several mechanisms taking place at the metal-molecule contact and experiments usually detect only the cumulative effects of these mechanisms, experimental techniques and contemporary firstprinciple calculations are suggested to be combined in order to derive a comprehensive picture of the interfacial electronic structure. Because of the lack of satisfactory analytic theory for the elucidation of the dependence of charge injection on temperature, electric field, and energetic disorder in organic (opto-)electronic devices, some important experimental results are discussed. Our recently introduced general methodology for extrapolating the nature of interfacial interactions is herein elaborated by analyzing the topological features of the electron density at the organic/metal bond critical points determined by the quantum theory of atoms in molecules. The beauty is that the interfacial interactions are given physical definitions without invoking more traditional and non-invariant concepts, such as individual orbitals.