ABSTRACT: In this study we investigate π-stacking interactions of a variety of aromatic heterocycles with benzene using dispersion corrected density functional theory. We calculate extensive potential energy surfaces for parallel-displaced interaction geometries. We find that dispersion contributes significantly to the interaction energy and is complemented by a varying degree of electrostatic interactions. We identify geometric preferences and minimum interaction energies for a set of 13 5- and 6-membered aromatic heterocycles frequently encountered in small drug-like molecules. We demonstrate that the electrostatic properties of these systems are a key determinant for their orientational preferences. The results of this study can be applied in lead optimization for the improvement of stacking interactions, as it provides detailed energy landscapes for a wide range of coplanar heteroaromatic geometries. These energy landscapes can serve as a guide for ring replacement in structure-based drug design.
Project description:Extremely extensive calculations of potential energy surfaces for the parallel-displaced configuration of pyridine dimer systems have been carried out using a dispersion-corrected density functional. Instead of focusing on stationary geometries these calculations provide much deeper insight into the "landscape" of the interaction energies of the particular systems-one can learn how the pyridine dimer stability changes along with various geometrical parameters. Other calculations such as natural bond orbital and energy decomposition have also been applied. The interplay of two significant factors, electrostatic forces and electron correlation effects, have been evaluated. The role of ?···? interactions in the stacked pyridine systems has also been confirmed, and surprisingly, this happened to be true even for the geometries where the formation of C-H···? interactions might be proposed instead. The combination of many different methods has revealed the complexity of the stacking interactions. Apart from providing a "literal new look" into pyridine interaction patterns another picture has emerged. A stacking interaction in a pyridine dimer system is perceived as a combination of many different sources of the interaction energy, including orbital ones, and this is true for many different geometries.
Project description:G-quadruplexes constitute a class of nucleic acid structures defined by stacked guanine tetrads (or G-tetrads) with guanine bases from neighboring tetrads stacking with one another within the G-tetrad core. Individual G-quadruplexes can also stack with one another at their G-tetrad interface leading to higher-order structures as observed in telomeric repeat-containing DNA and RNA. In this study, we investigate how guanine base stacking influences the stability of G-quadruplexes and their stacked higher-order structures. A structural survey of the Protein Data Bank is conducted to characterize experimentally observed guanine base stacking geometries within the core of G-quadruplexes and at the interface between stacked G-quadruplex structures. We couple this survey with a systematic computational examination of stacked G-tetrad energy landscapes using quantum mechanical computations. Energy calculations of stacked G-tetrads reveal large energy differences of up to 12 kcal/mol between experimentally observed geometries at the interface of stacked G-quadruplexes. Energy landscapes are also computed using an AMBER molecular mechanics description of stacking energy and are shown to agree quite well with quantum mechanical calculated landscapes. Molecular dynamics simulations provide a structural explanation for the experimentally observed preference of parallel G-quadruplexes to stack in a 5'-5' manner based on different accessible tetrad stacking modes at the stacking interfaces of 5'-5' and 3'-3' stacked G-quadruplexes.
Project description:In this study, the contributions of London dispersion forces to the strength of aromatic stacking interactions in solution were experimentally assessed using a small molecule model system. A series of molecular torsion balances were designed to measure an intramolecular stacking interaction via a conformational equilibrium. To probe the importance of the dispersion term, the size and polarizability of one of the aromatic surfaces were systematically increased (benzene, naphthalene, phenanthrene, biphenyl, diphenylethene, and diphenylacetylene). After correcting for solvophobic, linker, and electrostatic substituent effects, the variations due to polarizability were found to be an order of magnitude smaller in solution than in comparison to analogous computational studies in vacuo. These results suggest that in solution the dispersion term is a small component of the aromatic stacking interaction in contrast to their dominant role in vacuo.
Project description:We introduce a coarse-grained RNA model for molecular dynamics simulations, RACER (RnA CoarsE-gRained). RACER achieves accurate native structure prediction for a number of RNAs (average RMSD of 2.93?Å) and the sequence-specific variation of free energy is in excellent agreement with experimentally measured stabilities (R2?=?0.93). Using RACER, we identified hydrogen-bonding (or base pairing), base stacking, and electrostatic interactions as essential driving forces for RNA folding. Also, we found that separating pairing vs. stacking interactions allowed RACER to distinguish folded vs. unfolded states. In RACER, base pairing and stacking interactions each provide an approximate stability of 3-4?kcal/mol for an A-form helix. RACER was developed based on PDB structural statistics and experimental thermodynamic data. In contrast with previous work, RACER implements a novel effective vdW potential energy function, which led us to re-parameterize hydrogen bond and electrostatic potential energy functions. Further, RACER is validated and optimized using a simulated annealing protocol to generate potential energy vs. RMSD landscapes. Finally, RACER is tested using extensive equilibrium pulling simulations (0.86?ms total) on eleven RNA sequences (hairpins and duplexes).
Project description:Stacking interactions have been evaluated, employing computational methods, in dimers formed by analogous aliphatic and aromatic species of increasing size. Changes in stability as the systems become larger are mostly controlled by the balance of increasing repulsion and dispersion contributions, while electrostatics plays a secondary but relevant role. The interaction energy increases as the size of the system grows, but it does much faster in ?-? dimers than in ?-? complexes and more remarkably than in ?-? dimers. The main factor behind the larger stability of aromatic dimers compared to complexes containing aliphatic molecules is related to changes in the properties of the aromatic systems due to electron delocalization leading to larger dispersion contributions. Besides, an extra stabilization in ?-? complexes is due to the softening of the repulsive wall in aromatic species that allows the molecules to come closer.
Project description:The widespread presence of aromatic stacking interactions in chemical and biological systems, combined with their relatively small energetic contribution, have led to a plethora of theoretical and experimental studies for their quantification and rationalization. Typically, π-π aromatic interactions are studied as a function of substituents to gather information about the interaction mechanism. While experiments suggest that aromatic interactions are dominated by local electrostatic contacts between π-electron density and CH groups, theoretical work has raised the possibility that direct electrostatic interactions between local dipoles of the substituents may play a role. We describe a supramolecular cage that binds two aromatic carboxylates in a stacked geometry such that the aromatic substituents are remote in space. Chemical Double Mutant Cycles (DMCs) were used to measure fifteen different aromatic stacking interactions as a function of substituent (NMe2, OMe, Me, Cl and NO2). When both aromatic rings have electron-withdrawing nitro substituents, the interaction is attractive (-2.8 kJ mol-1) due to reduced π-electron repulsion. When both aromatic rings have electron-donating di-methylamino substituents, the interaction is repulsive (+2.0 kJ mol-1) due to increased π-electron repulsion. The results show that aromatic stacking interactions are dominated by short range electrostatic contacts rather than substituent dipole interactions.
Project description:Interactions between polar atoms are challenging to model because at very short ranges they form hydrogen bonds (H-bonds) that are partially covalent in character and exhibit strong orientation preferences; at longer ranges the orientation preferences are lost, but significant electrostatic interactions between charged and partially charged atoms remain. To simultaneously model these two types of behavior, we refined an orientation dependent model of hydrogen bonds [Kortemme et al. J. Mol. Biol. 2003, 326, 1239] used by the molecular modeling program Rosetta and then combined it with a distance-dependent Coulomb model of electrostatics. The functional form of the H-bond potential is physically motivated and parameters are fit so that H-bond geometries that Rosetta generates closely resemble H-bond geometries in high-resolution crystal structures. The combined potentials improve performance in a variety of scientific benchmarks including decoy discrimination, side chain prediction, and native sequence recovery in protein design simulations and establishes a new standard energy function for Rosetta.
Project description:An efficient route to substituted N-fused aromatic heterocycles, including indolizines, imidazo[1,2-a]pyridines, and imidazo[1,5-a]pyridines from azole aldehydes, is reported. Wittig olefination of the aldehydes with fumaronitrile and triethylphosphine affords predominantly E-alkenes that undergo rapid cyclization upon treatment with a mild base. Substituent control of the 1-, 2-, and 3-positions of the resulting heteroaromatic bicycles is shown. Alternatively, the isolable E-alkene undergoes selective alkylation with electrophiles, followed by in situ annulation to indolizines additionally substituted at the 6-position.
Project description:Unlike typical hydrogen-bonded networks such as water, hydrogen bonded ionic liquids display some unusual characteristics due to the complex interplay of electrostatics, polarization, and dispersion forces in the bulk. Protic ionic liquids in particular contain close-to traditional linear hydrogen bonds that define their physicochemical properties. This work investigates whether hydrogen bonded ionic liquids (HBILs) can be differentiated from aprotic ionic liquids with no linear hydrogen bonds using state-of-the-art ab initio calculations. This is achieved through geometry optimizations of a series of single ion pairs of HBILs in the gas phase and an implicit solvent. Using benchmark CCSD(T)/CBS calculations, the electrostatic and dispersion components of the interaction energy of these systems are compared with those of aprotic ionic liquids. The inclusion of the implicit solvent significantly influenced geometries of single ion pairs, with the gas phase shortening the hydrogen bond to reduce electrostatic interactions. HBILs were found to have stronger interactions by at least 10EtMeNH0 kJ mol-1 over aprotic ILs, clearly highlighting the electrostatic nature of hydrogen bonding. Geometric and energetic parameters were found to complement each other in determining the extent of hydrogen bonding present in these ionic liquids.
Project description:Adsorption of seven 5-membered N-heterocycles on B/N/BN-doped graphene (with coronene as a model system) has been studied using density functional theory (DFT). The geometry of the complexes validated the involvement of both ?···? stacking and N-H···? interaction in the adsorption process. The stability of the complexes is measured in terms of stabilization energy, and the results suggested that the complexes are stable enough (stabilization energies are in the range of 7.61-14.77 kcal mol-1). Studies confirmed the stability of complexes in the solvent phase too irrespective of the dielectric of the solvent. Dispersive force is the major mode of interaction in stabilizing the complexes. Natural bond orbital analysis indicated a small contribution from electrostatic and covalent interactions. Thermochemical analysis revealed that the complexation is exothermic in nature and favorable at a lower temperature. Adsorption of N-heterocycles exerts a nominal impact on the electronic properties of the undoped/doped graphene. The study presents a simple approach to introduce an arbitrary functionality to undoped/doped graphene by preserving its electronic properties.