Kinetic Barrier to Enzyme Inhibition Is Manipulated by Dynamical Local Interactions in E. coli DHFR.

Dihydrofolate reductase (DHFR) is an important drug target and a highly studied model protein for understanding enzyme dynamics. DHFR's crucial role in folate synthesis renders it an ideal candidate to understand protein function and protein evolution mechanisms. In this study, to understand how a newly proposed DHFR inhibitor, 4'-deoxy methyl trimethoprim (4'-DTMP), alters evolutionary trajectories, we studied interactions that lead to its superior performance over that of trimethoprim (TMP). To elucidate the inhibition mechanism of 4'-DTMP, we first confirmed, both computationally and experimentally, that the relative binding free energy cost for the mutation of TMP and 4'-DTMP is the same, pointing the origin of the characteristic differences to be kinetic rather than thermodynamic. We then employed an interaction-based analysis by focusing first on the active site and then on the whole enzyme. We confirmed that the polar modification in 4'-DTMP induces additional local interactions with the enzyme, particularly, the M20 loop. These changes are propagated to the whole enzyme as shifts in the hydrogen bond networks. To shed light on the allosteric interactions, we support our analysis with network-based community analysis and show that segmentation of the loop domain of inhibitor-bound DHFR must be avoided by a successful inhibitor.

Engineering supramolecular helical assemblies via interplay between carbon(sp) tetrel and halogen bonding interactions.

Building supramolecular helical structures is a challenge due to difficulties in the design and control of competitive noncovalent forces. Herein, we report three scaffolds (1a, 1b, and 1c) decorated with -CN and -Br groups. These groups known for their ability to form multiple noncovalent interactions and with efficient design can be utilized to achieve such complex structures. X-Ray analyses revealed that the crystal packing of 1a, 1b and 1c is dominated by highly directional Br⋯CN Csp-tetrel bonding (1a), Br⋯π, Br⋯N (1b) and Br⋯Br (1c) XB interactions, and these interactions have led to the formation of achiral P/M, chiral M and achiral P/M helical assemblies, respectively. A detailed structural and computational analysis was performed to clarify the nature and estimate the strength of these interactions in helical assemblies. MEP analyses of 1a, 1b, and 1c have shown that the potential of electron-deficient and electron-rich regions within the structures has similar values. Yet, the geometric accessibility of σ-holes has differed with each scaffold. Thus, dominant interactions have changed and consequently led to different helical assembly formations. The interaction energies are around -11.4 (1a), -4.0 (1b), and -4.6 (1c) kcal mol-1 and mainly driven by dispersion, followed by electrostatic interactions. To our surprise, the Csp-tetrel bonding (1a), considered the weakest among non-covalent interactions, is the strongest interaction among the three scaffolds, which shows the importance of accessibility of Sigma holes. These findings are expected to contribute to the future rational design of complex self-assembled materials, utilizing Csp-tetrel and XB interactions, in various applications such as crystal engineering, organic semiconductors, sensor devices, and medicinal chemistry.

The chemical and electrochemical stimuli viologen substituted phthalocyanine with tunable optical features1.

In this study, viologen-tetrasubstituted Zn(II) phthalocyanines (PcV1 and PcV2) were designed and synthesized to achieve the tunable optical features via redox-active viologen groups. Several parameters relevant to the evaluation of the tunable optical features have been investigated: UV-Vis, cyclic voltammetry (CV), EPR, square wave voltammetry (SWV), and theoretical analyses. The results showed that upon reductions and oxidations of viologen groups either chemically or electrochemically, the optical features of PcV1 and PcV2 change drastically with switchable processes. These outcomes indicate that achieving control over optical features of large organic chromophores such as Pc with our rational design can be used for the design of new complex organic electronic materials.

Investigation of iron release from the N- and C-lobes of human serum transferrin by quantum chemical calculations.

Human serum transferrin binds ferric ions with high affinity and delivers them into cells via receptor-mediated endocytosis upon a decrease in pH in the endosome. Protonation events and conformational changes are known to play an important role in iron-release though the release is not yet fully understood. Human serum transferrin consists of two similar lobes which release iron at different rates. In this study, we investigate the iron binding sites of N- and C-lobes using quantum mechanical tools, particularly, the quantum chemical cluster approach. This study supports the inevitable role of axial tyrosine for the release of iron in quantum chemical models and provides valuable information about the proton transfer pathways for the protonation of Tyr188 and Tyr517 in N- and C-lobes, respectively. The calculations show that the release process is similar in both lobes; however, the energetic differences of the release process in N- and C-lobes, demonstrated for the first time, indicated that the release of iron in the N-lobe is thermodynamically favorable, in contrast to the one in the C-lobe.

Theoretical Investigation of the Biogenetic Pathway for Formation of Antibacterial Indole Alkaloids from Voacanga africana.

The energetic viability of the previously proposed biogenetic pathway for the formation of two unique monoterpenoid indole alkaloids, voacafricine A and B, which are present in the fruits of Voacanga africana, was investigated using density functional theory computations. The results of these calculations indicate that not only is the previously suggested pathway not energetically viable but also that an alternative biosynthetic precursor is likely.

Halogen-Bonded BODIPY Frameworks with Tunable Optical Features*.

The ability to tune the optical features of BODIPY materials in the solid state is essential for their photorelated application and requires efficient control of the crystal packing. In this study, such control of BODIPY supramolecular assemblies was achieved by deliberate design and synthesis of a BODIPY containing a strong halogen-bond (XB) acceptor (-NO2 ) and donor (I, Br) to mediate XB interactions. The di-halogenated structures formed isostructural mono-coordinate motif B3, B4 (1D tubular structure) and symmetric bifurcated motif B4-II (1D zigzag chains structure) through N-O⋅⋅⋅I, Br XB interactions. These XB interactions promote singlet-to-triplet intersystem crossing and triplet-to-singlet reverse intersystem crossing due to partial delocalization of oxygen electrons onto Br and I, which leads to unexpected fluorescence enhancement of B4-II. Finally, the indirect optical band gaps of B3, B4 and B4-II were amenable to tuning in the range of 1.85-2.50 eV by XB-driven crystal packings.

Influence of odd-even effect and intermolecular interactions in 2D molecular layers of bisamide organogelators.

Organogelators have a wide range of use in everyday life including drug delivery and controlled release, surface coating and paper industry. In this study, a series of model bisamides have been analyzed as potential organogelators. These molecules are connected by odd and even numbered methylene units (n) in length ranging from 2 to 9. By constructing layers of those molecules along the growth direction we provide an insight into the self-assembly process. A complete systematic analysis of the computational results with B3LYP/6-311+G** suggests that the self-assembly of these potential organogelators is influenced by the odd-even effect, the relative direction of amide carbonyl groups, the bridging spacer chain length and the presence of a chiral alpha carbon. The aforementioned factors alter the strength of the intermolecular hydrogen bonds as well as the van der Waals interactions, which in turn may affect the self-assembly process of gelation and result in the formation of aggregates with different shapes. It is found that molecules with short central chains have an energetic preference for antiparallel arrangement over their parallel analogues as a result of stronger hydrogen bonding interactions. As the central chain elongates, the free energy difference between antiparallel and parallel structures decreases suggesting a compromise between hydrogen bonding and van der Waals interactions. The complete structural analysis suggests ribbon-like structures for achiral even-antiparallel and woven-like structures for odd-parallel systems, respectively. Upon creation of asymmetry on the alpha carbon, a twisted ribbon-like and a coiled coil-like structure are observed for even and odd systems, respectively. Our computational results are in accordance with the experimental results and provide an insight into the self-assembly of layers of bisamides.

1,3-Dipolar Cycloaddition Reactions of Low-Valent Rhodium and Iridium Complexes with Arylnitrile N-Oxides.

The reactions between low-valent Rh(I) and Ir(I) metal-carbonyl complexes and arylnitrile oxides possess the electronic and structural features of 1,3-dipolar cycloadditions. Density functional theory (DFT) calculations on these reactions, involving both cyclopentadienyl and carboranyl ligands on the metal carbonyl, explain the ease of the chemical processes and the stabilities of the resulting metallaisoxazolin-5-ones. The metal-carbonyl bond has partial double bond character according to the Wiberg index calculated through NBO analysis, and so the reaction can be considered a normal 1,3-dipolar cycloaddition involving M═C bonds. The rates of formation of the metallacycloadducts are controlled by distortion energy, analogous to their organic counterparts. The superior ability of anionic Ir complexes to share their electron density and accommodate higher oxidation states explains their calculated higher reactivity toward cycloaddition, as compared to Rh analogues.

Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions.

Remarkable progress in the area of asymmetric organocatalysis has been achieved in the last decades. Cinchona alkaloids and their derivatives have emerged as powerful organocatalysts owing to their reactivities leading to high enantioselectivities. The widespread usage of cinchona alkaloids has been attributed to their nontoxicity, ease of use, stability, cost effectiveness, recyclability, and practical utilization in industry. The presence of tunable functional groups enables cinchona alkaloids to catalyze a broad range of reactions. Excellent experimental studies have extensively contributed to this field, and highly selective reactions were catalyzed by cinchona alkaloids and their derivatives. Computational modeling has helped elucidate the mechanistic aspects of cinchona alkaloid catalyzed reactions as well as the origins of the selectivity they induce. These studies have complemented experimental work for the design of more efficient catalysts. This Account presents recent computational studies on cinchona alkaloid catalyzed organic reactions and the theoretical rationalizations behind their effectiveness and ability to induce selectivity. Valuable efforts to investigate the mechanisms of reactions catalyzed by cinchona alkaloids and the key aspects of the catalytic activity of cinchona alkaloids in reactions ranging from pharmaceutical to industrial applications are summarized. Quantum mechanics, particularly density functional theory (DFT), and molecular mechanics, including ONIOM, were used to rationalize experimental findings by providing mechanistic insights into reaction mechanisms. B3LYP with modest basis sets has been used in most of the studies; nonetheless, the energetics have been corrected with higher basis sets as well as functionals parametrized to include dispersion M05-2X, M06-2X, and M06-L and functionals with dispersion corrections. Since cinchona alkaloids catalyze reactions by forming complexes with substrates via hydrogen bonds and long-range interactions, the use of split valence triple-ζ basis sets including diffuse and polarization functions on heavy atoms and polarization functions on hydrogens are recommended. Most of the studies have used the continuum-based models to mimic the condensed phase in which organocatalysts function; in some cases, explicit solvation was shown to yield better quantitative agreement with experimental findings. The conformational behavior of cinchona alkaloids is also highlighted as it is expected to shed light on the origin of selectivity and pave the way to a comprehensive understanding of the catalytic mechanism. The ultimate goal of this Account is to provide an up-to-date overlook on cinchona alkaloid catalyzed chemistry and provide insight for future studies in both experimental and theoretical fields.

A Theoretical Study of the Mechanism of the Desymmetrization of Cyclic meso-Anhydrides by Chiral Amino Alcohols.

The alcoholysis of cyclic meso-anhydrides catalyzed by ß-amino alcohols has been investigated with DFT quantum mechanics to determine the mechanism of this reaction. Both nucleophilic catalysis and general base catalysis pathways are explored for methanol-induced ring opening of an anhydride catalyzed by a chiral amino alcohol. The nucleophilic pathway involves a late transition state with a high energy barrier. In this mechanism, methanolysis is expected to take place following the amine-induced ring opening of the anhydride. In the base-catalyzed mechanism, methanol attack on one carbonyl group of the meso-anhydride is assisted by the ß-amino alcohol; the amine functionality abstracts the methanol proton. The chiral amino alcohol also catalyzes the reaction by stabilizing the oxyanion that forms upon ring opening of the anhydride by hydrogen bonding with its alcoholic moiety. Both stepwise and concerted pathways have been studied for the general base catalysis route. Transition structures for both are found to be lower in energy than in the nucleophilic mechanism. Overall this study has shed light on the mechanism of the ß-amino alcohol-catalyzed alcoholysis of cyclic meso-anhydrides, showing that the nucleophilic pathway is approximately 100 kJ mol(-1) higher in energy than the general base pathway.