Intramolecular Interaction Energies Research Articles

The Limit of Intramolecular H-Bonding.

Hydrogen bonds are ubiquitous interactions in molecular recognition. The energetics of such processes are governed by the competing influences of pre-organization and flexibility that are often hard to predict. Here we have measured the strength of intramolecular interactions between H-bond donor and acceptor sites separated by a variable linker. A striking distance-dependent threshold was observed in the intramolecular interaction energies. H-bonds were worth less than -1 kJ mol-1 when the interacting groups were separated by ≥6 rotating bonds, but ranged between -5 and -9 kJ mol-1 for ≤5 rotors. Thus, only very strong external H-bond acceptors were able to compete with the stronger internal H-bonds. In addition, a constant energetic penalty per rotor of ∼5-6 kJ mol-1 was observed in less strained situations where the molecule contained ≥4 rotatable bonds.

On the Stability of Cyclophane Derivates Using a Molecular Fragmentation Method.

A molecular fragmentation method is used to study the stability of cyclophane derivates by decomposing the molecular energy into the molecular strain and intramolecular interaction energies. The molecular strain energies obtained by utilising the fragmentation method are in good agreement with existing experimental data. The intramolecular interaction energies calculated as the difference between the supermolecular energy and the bonded fragment energies are repulsive in the cyclophanes studied. The nature of this interaction is studied for groups of systematically extended doubled layered paracyclophane systems using the random-phase approximation (RPA), two recently developed extensions to the RPA and standard density functional theory (DFT) methods including dispersion corrections. Upon a systematic increase in conjugation the strongly repulsive intramolecular interaction energy reduces and thus leads to an increase in the stability. Finally, existing experimental and theoretical estimates of the molecular strain are compared with the results of this work.

Molecular structure and DFT investigations on new cobalt(II) chloride complex with superbase guanidine type ligand

The new [Co(btmgn)Cl 2] complex and the 1,8-bis(tetramethylguanidino)naphthalene (btmgn) ligand were synthesized and characterized. The X-ray single crystal investigation showed distorted tetrahedral geometry around the Co(II) ion. The geometry of the btmgn and [Co(btmgn)Cl 2] complex was optimized using the B3LYP/6–311G(d,p) method. The calculated geometric parameters at the optimized structure of the [Co(btmgn)Cl 2] complex showed good agreement with our reported X-ray structure. The two tetramethylguanidino groups are in a cis-type position to the naphthalene ring plane both in the free and coordinated btmgn. The large red shift of the υ C=N mode upon coordination indicates the strong ligand–metal interactions. The calculated natural charges using natural bond orbital (NBO) analysis at the two coordinated Cl-atoms are not equivalent. Also the two LP(4)Cl →LP*(3)Co intramolecular charge transfer interaction energies (E (2)) are 29.00 and 39.17 kcal/mol, respectively. The two Co-Cl bonds are not equivalent where the longer Co-Cl bond has more electronegative chlorine atom than the shorter one. Molecular electrostatic potential (MEP) study of the btmgn ligand showed that the N4 and N7 atoms are the most reactive nucleophilic centers for the coordination with the Co 2+ ion. The [Co(btmgn)Cl 2] complex has higher polarizability (α 0), first hyperpolarizability (β 0) and lower energy gap (ΔE) than the free ligand. The TD-DFT calculations predicted the transition bands at 337.2 nm (f =0.2299, H →L) and 342.6 nm (f =0.1465, H-2/H →L) for the btmgn and [Co(btmgn)Cl 2], respectively. Cobalt(II) complex of 1,8-bis(tetramethylguanidino)naphthalene superbase showed distorted coordination geometry. The DFT calculations indicated that the ligand has two strongly basic guanidinic N-atoms available for coordination with the metal ion.

Experimental and theoretical spectroscopic studies, HOMO–LUMO, NBO analyses and thione–thiol tautomerism of a new hybrid of 1,3,4-oxadiazole-thione with quinazolin-4-one

The hybrid 3-(4-chlorophenyl)-2-[(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methylthio]quinazolin-4(3H)-one has been synthesized and characterized using elemental analysis, FTIR and NMR spectroscopy. The thione–thiol tautomeric equilibria has been studied using both DFT/B3LYP and HF methods at different basis sets. The results of calculations showed predominance of the thione form. The molecular structure and vibrational spectra of the stable tautomer are predicted using the same level of theory. The complete assignments of the vibrational modes were performed on the basis of potential energy distribution (PED). The 6-311++G(d,p) gave the best results compared to the experimental data. The chemical shift values of the two tautomers are calculated using GIAO method. The NH proton of the thione tautomer have chemical shift value closer to the experimental data compared to the SH proton of the thiol one. The electronic transitions are predicted using the TD-DFT calculations at B3LYP/6-311++G(d,p) level of theory. The calculated polarizability and first hyperpolarizability showed that the studied compound has better NLO properties than urea. The molecular electrostatic potential (MEP) analysis reveals the sites for electrophilic and nucleophilic attack in the molecule. NBO analysis is carried out to investigate the stabilization energy of various intramolecular charge transfer interactions within the studied molecule.

Physicochemical origin of high correlation between thermal stability of a protein and its packing efficiency: a theoretical study for staphylococcal nuclease mutants.

There is an empirical rule that the thermal stability of a protein is related to the packing efficiency or core volume of the folded state and the protein tends to exhibit higher stability as the backbone and side chains are more closely packed. Previously, the wild type and its nine mutants of staphylococcal nuclease were compared by examining their folded structures. The results obtained were as follows: The stability was not correlated with the number of intramolecular hydrogen bonds, intramolecular electrostatic interaction energy, or degree of burial of the hydrophobic surface; though the empirical rule mentioned above held, it was not the proximate cause of higher stability; and the number of van der Waals contacts NvdW, or equivalently, the intramolecular van der Waals interaction energy was an important factor governing the stability. Here we revisit the wild type and its nine mutants of staphylococcal nuclease using our statistical-mechanical theory for hydration of a protein. A molecular model is employed for water. We show that the pivotal factor is the magnitude of the water-entropy gain upon folding. The gain originates from an increase in the total volume available to the translational displacement of water molecules coexisting with the protein in the system. The magnitude is highly correlated with the denaturation temperature Tm. Moreover, the apparent correlation between NvdW and Tm as well as the empirical rule is interpretable (i.e., their physicochemical meanings can be clarified) on the basis of the water-entropy effect.

Synthesis, molecular structure investigations and antimicrobial activity of 2-thioxothiazolidin-4-one derivatives

A variety of 2-thioxothiazolidin-4-one derivatives were prepared and their in vitro antimicrobial activities were studied. Most of these compounds showed significant antibacterial activity specifically against Gram-positive bacteria, among which compounds 4a,e,g, 5b,e,g,h and 6f exhibit high levels of antimicrobial activity against Bacillus subtilis ATCC 10400 with Minimum Inhibitory Concentration (MIC) value of 16μg/mL. All compounds have antifungal activity against Candida albicans. Unfortunately, however, none of the compounds were active against Gram-negative bacteria. The chemical structure of 3 was confirmed by X-ray single crystal diffraction technique. DFT calculations of 3 have been performed on the free C10H7Cl2NO2S2, 3a and the H-bonded complex, C10H7Cl2NO2S2·H2O, 3b to explore the effect of the H-bonding interactions on the geometric and electronic properties of the studied systems. A small increase in bond length was observed in the C12–O6 due to the H-bonding interactions between 3a and water molecule. MEP study has been used to recognize the most reactive sites towards electrophilic and nucleophilic attacks as well as the possible sites for the H-bonding interactions. The TD-DFT calculations have been used to predict theoretically the electronic spectra of the studied compound. The most intense transition band is predicted at 283.9nm due to the HOMO-2/HOMO-1 to LUMO transitions. NBO analyses were carried out to investigate the stabilization energy of the various intramolecular charge transfer interactions within the studied molecules.

Exploration of zeroth-order wavefunctions and energies as a first step toward intramolecular symmetry-adapted perturbation theory

Non-covalent interactions occur between and within all molecules and have a profound impact on structural and electronic phenomena in chemistry, biology, and material science. Understanding the nature of inter- and intramolecular interactions is essential not only for establishing the relation between structure and properties, but also for facilitating the rational design of molecules with targeted properties. These objectives have motivated the development of theoretical schemes decomposing intermolecular interactions into physically meaningful terms. Among the various existing energy decomposition schemes, Symmetry-Adapted Perturbation Theory (SAPT) is one of the most successful as it naturally decomposes the interaction energy into physical and intuitive terms. Unfortunately, analogous approaches for intramolecular energies are theoretically highly challenging and virtually nonexistent. Here, we introduce a zeroth-order wavefunction and energy, which represent the first step toward the development of an intramolecular variant of the SAPT formalism. The proposed energy expression is based on the Chemical Hamiltonian Approach (CHA), which relies upon an asymmetric interpretation of the electronic integrals. The orbitals are optimized with a non-hermitian Fock matrix based on two variants: one using orbitals strictly localized on individual fragments and the other using canonical (delocalized) orbitals. The zeroth-order wavefunction and energy expression are validated on a series of prototypical systems. The computed intramolecular interaction energies demonstrate that our approach combining the CHA with strictly localized orbitals achieves reasonable interaction energies and basis set dependence in addition to producing intuitive energy trends. Our zeroth-order wavefunction is the primary step fundamental to the derivation of any perturbation theory correction, which has the potential to truly transform our understanding and quantification of non-bonded intramolecular interactions.

Minimizing Density Functional Failures for Non-Covalent Interactions Beyond van der Waals Complexes

CONSPECTUS: Kohn-Sham density functional theory offers a powerful and robust formalism for investigating the electronic structure of many-body systems while providing a practical balance of accuracy and computational cost unmatched by other methods. Despite this success, the commonly used semilocal approximations have difficulties in properly describing attractive dispersion interactions that decay with R(-6) at large intermolecular distances. Even in the short to medium range, most semilocal density functionals fail to give an accurate description of weak interactions. The omnipresence of dispersion interactions, which are neglected in the most popular electronic structure framework, has stimulated intense developments during the past decade. In this Account, we summarize our effort to develop and implement dispersion corrections that dramatically reduce the failures of both inter- and intramolecular interaction energies. The proposed schemes range from improved variants of empirical atom pairwise dispersion correction (e.g., dD10) to robust formulations dependent upon the electron density. Emphasis has been placed on introducing more physics into a modified Tang and Toennies damping function and deriving accurate dispersion coefficients. Our most sophisticated and established density-dependent correction, dDsC, is based on a simple generalized gradient approximation (GGA)-like reformulation of the exchange hole dipole moment introduced by Becke and Johnson. Akin to its empirical precursor, dDsC dramatically improves the interaction energy of a variety of standard density functionals simultaneously for typical intermolecular complexes and shorter-range interactions occurring within molecules. The broad applicability and robustness of the dDsC scheme is demonstrated on various representative reaction energies, geometries, and molecular dynamic simulations. The suitability of the a posteriori correction is also established through comparisons with the more computationally demanding self-consistent implementation. The proposed correction is then exploited to identify the key factors at the origin of the errors in thermochemistry beyond van der Waals complexes. Particular focus is placed on charge-transfer and mixed-valence complexes, which are relevant to the field of organic electronics. These types of complexes represent insightful examples for which the delocalization error may partially counterbalance the missing dispersion. Our devised methodology reveals the true performance of standard density functional approximations and the subtle interplay between the two types of errors. The analysis presented provides guidance for future functional development that could further improve the modeling of the structures and properties of molecular materials. Overall, the proposed state-of-the-art approaches have contributed to stress the crucial role of dispersion and improve their description in both straightforward van der Waals complexes and more challenging chemical situations. For the treatment of the latter, we have also provided relevant insights into which type of density functionals to favor.

In silico identification of the active conformation of open-chain enaminones with anticonvulsant activity

A study about the relationship between molecular properties of open-chain enaminones and their anticonvulsant activity is presented in this paper. Geometry optimizations of the enaminones were performed at HF and DFT/B3LYP levels of theory using 6-31 + G(d) basis set. The HOMO and LUMO energies were obtained at the same level of theory. The solvent effect was studied through IPCM. A natural bond orbital (NBO) analysis was performed to analyze the possible association between the stability and the intramolecular hydrogen bond interaction energies. The stability order of the isomers in gas phase was the following: cis-1 > trans-4 > cis-2 > trans-3. The IPCM method showed that the trans-3 isomers are more stable that the cis-2 when the solvent effect was taken into account. Two important intramolecular hydrogen bonds were found by NBO analysis. According to our findings, these interactions could affect the activity of the two most stable isomers (cis-1 and trans-4). By contrast, trans-3 isomers did not present this type of interaction. Therefore, the latter isomers have a large flexibility and can adopt a conformation similar to the conformation of active ringed enaminones. In addition, HOMO and LUMO energies suggested that the trans-3 isomers could be the most reactive species.

Reaction Dynamics of CH3+ HBr → CH4+ Br at 150-1000 K

The kinetics of the radical-polar molecule reaction CH3 + HBr → CH4 + Br has been studied at temperatures between 150 and 1000 K using classical dynamics procedures. Potential energy surfaces constructed using analytical forms of inter- and intramolecular interaction energies show a shallow well and barrier in the entrance channel, which affect the collision dynamics at low temperatures. Different collision models are used to distinguish the reaction occurring at low- and high-temperature regions. The reaction proceeds rapidly via a complex-mode mechanism below room temperature showing strong negative temperature dependence, where the effects of molecular attraction, H-atom tunneling and recrossing of collision complexes are found to be important. The temperature dependence of the rate constant between 400 and 1000 K is positive, the values increasing in accordance with the increase of the mean speed of collision. The rate constant varies from 7.6 × 10 −12 at 150 K to 3.7 × 10 −12 at 1000 K via a minimum value of 2.5 × 10 −12 cm 3 molecule −1 s −1 at 400 K.

A Minimal Implementation of the AMBER-PAICS Interface for Ab Initio FMO-QM/MM-MD Simulation

Abstract For the purpose of providing a realistic description of the reaction mechanisms in large molecular systems, we propose a quantum mechanical/molecular mechanical (QM/MM) method combined with the ab initio fragment molecular orbital (FMO) method, i.e., the ab initio FMO-QM/MM method. By connecting a molecular dynamics (MD) program AMBER with an FMO program PAICS, we have implemented an AMBER-PAICS interface (AP-IF). Using the AP-IF, we demonstrate three example applications: (a) a hydrogen fluoride and water molecular clusters, (b) an alanine dipeptide in aqueous solution, and (c) a prion protein–GN8 complex. From these results, it is confirmed that the FMO-QM/MM method offers a good compromise between chemical accuracy and computational cost and enables us to obtain in ab initio quality the inter- and intramolecular interaction energies between molecules or residues in large molecular systems such as solution and biomolecule, by using the dynamics-based interfragment interaction energy (IFIE) analysis.

Theoretical investigation of the substituent effects in the conformational isomerism of bromoalkoxycyclohexanes

Isodesmic reactions and the energy of intramolecular interactions in bromoalkoxycyclohexanes (alkoxy=OMe, OEt, OiPr and OtBu) were computed to evaluate the effect of bromine and alkoxy groups when bonded together in a cyclohexane ring to give cis and trans-1,2, 1,3 and 1,4 isomers. According to the enthalpy energies obtained from the isodesmic reactions, the bromine atom is preferred to be introduced axially in methoxycyclohexane to give trans-1-bromo-2-methoxycyclohexane; otherwise, equatorial introduction of the bromine atom is favoured. Either direct or indirect intramolecular interactions involving OR and Br, obtained from comparison with the conformational energies of the monosubstituted cyclohexanes, indicate a preference for bromine axially oriented, except for the cis-1,3 isomer, in which the OR and Br groups experience high steric hindrance to each other. The effect of R is generally invariant.

Molecular Dynamics Studies of Protein Targets for Cancer

In this meeting, we present the molecular dynamics studies of two protein targets for cancers. The one is epiregulin (EPR), which is a member of the epidermal growth factor family and a factor affecting pancreatic cancer. Recently, it was observed that the binding affinity of EPR without S-S bonds for an antibody is lower than that of EPR with S-S bonds, and that the affinity of a long form type (extracellular domain) of EPR without S-S bonds is higher than that of a mature type without S-S bonds. To investigate the effect of the S-S bonds on the structural stability of EPR, we have performed molecular dynamics (MD) simulation for these three types of EPR. From our simulations, it has found that the S-S bonds reduce the structural fluctuation of EPR, and the structure of the mature domain in the long form type is similar to the mature type with S-S bonds.The other protein target is the loop region between fibronectin type III domains of roundabout-1 that is a receptor for Slit1 and Slit2 in axon growth cones and differentially expressed in cancers. We have investigated the structural stability and thermodynamic property of the loop region using MD simulation. We have calculated two types of peptide of different size: the peptide composed of 26 amino acid residues corresponding to the full region of the fluctuating loop, and the shorter one of 20 amino acid residues. In the 20 amino acid peptide calculations, we have observed two different stable conformations, which are stable during more than 1.5 μs. We have found that for the one conformation, the intramolecular interaction energy contributes to the thermodynamical stability, while for the other one, water binding to the turn part of the peptide is dominant contribution.

Structural stability of nano-sized crystals of HMX: A molecular dynamics simulation study

The interaction potential energy and heat of sublimation of nanoparticles of HMX crystal polymorphs are studied by using molecular dynamics methods with a previously developed force field [Bedrov, et al., J. Comput.-Aided Mol. Des. 8 (2001) 77]. Molecular dynamics simulations of nanoparticles with 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 molecules of HMX are carried out at 300K. The intermolecular, intramolecular and total interaction energies per mole for the nanoparticles are calculated at 300K. Then, we have calculated sublimation enthalpy of HMX crystal polymorphs with different sizes. For the all sizes, the β-HMX is found to be the most stable phase, due to having the least total interaction energy. Also, α-HMX is more stable than δ-HMX. An increase in the sublimation enthalpy with the size of the nanoparticle can be seen.

Relationship between Melting Point and the Interaction Energy of Alkyl Imidazolium Tetrafluoroborate Ionic Liquids

Eleven types of alkyl imidazolium tetrafluoroborate ionic liquids(ILs) have been investigated using the density functional theory(DFT) B3LYP method together with basis set 6-311++G(d,p).First,we performed geometry optimization of the ion system {[XIM][BF4]n}(n-1)-(n=2,3),which is composed of one alkyl imidazolium cation XIM+ and two or three BF4-anions.Then the intramolecular interaction energies were calculated for those structures with the lowest energies,and the basis set superposition error was corrected by the counterpoise method.The relationship between the experimental melting points and the interaction energies was also investigated.A linear correlation was found for the alkyl imidazolium tetrafluoroborate compounds studied,which was also consistent with the linear correlation previously found for amino acid cation based ILs.Our work shows the possibility of designing ILs with the help of quantum chemistry in the future.

Interaction Analysis of the Native Structure of Prion Protein with Quantum Chemical Calculations.

We examined the solvent interaction and intramolecular interaction of the native structure of prion protein (PrP) using quantum chemical calculations based on the fragment molecular orbital (FMO) method. The influence due to the geometrical fluctuation was taken into account by performing calculations on forty different conformations. Each FMO calculation was carried out at the MP2 level of theory with the cc-pVDZ in which the resolution of the identity approximation was employed to reduce the computational cost. The solvent interaction energies obtained from the calculations provided information about the hydrophilicity of the three α-helices. We examined the roles of the charged residues in retaining the native structure of PrP with the calculated intramolecular interaction energies. The analysis, focused on van der Waals interaction, showed that the hydrophobic residues were important for the stability of the native structure. Our results were also discussed in relation to the identified pathogenetic mutations of prion diseases. Additionally, we examined the distribution of the calculated values with 40 structures, in which we demonstrated the influence of geometrical fluctuations on quantum chemical calculations.

Theoretical studies on the conformation of peptides in solution I. Conformation of N-acetyl glycine N-methyl amide in solution

A theoretical prediction of the most preferred conformation of N-acetyl glycine N-methyl amide in CCl4 is attempted. The calculation of the intrinsic or intramolecular interaction energies employs the method of partitioned energy potential. The intramolecular electrostatic energies include terms up to octopole segmental moments. It is pointed out that a truncation of the multipole interaction series at the monopole term is unjustified in this case. The calculation of intermolecular interactions with the environment is based on the method of continuum reaction field, including electrostatic, dispersion and cavity terms, which depend on the conformations through molecular dipole moments, molecular volume, and molecular exposed surface area. The most stable conformation predicted in this study (Φ = 255°, Φ = 105°) closely corresponds to the minimum in intramolecular electrostatic interactions. For other solvents intramolecular interactions and solvent effects may be of comparable importance in determining the most stable conformation of the solute molecule.

Thermal stability of proteins does not correlate with the energy of intramolecular interactions

Small monomeric proteins from mesophilic and thermophilic organisms were studied. They have close structural and physical and chemical properties but vary in thermal stability. A thermodynamic analysis of heat unfolding was made and integral enthalpy of unfolding (Δ H unf), heat capacity of hydration (Δ C p hyd) and enthalpy of hydration (Δ H hyd) and of the buried surface area (ΔASA) of nonpolar and polar groups as well as the enthalpy of disruption of intramolecular interaction (Δ H int in gas phase) at 298 K were determined. The absence of correlation between protein thermostability and energetic components suggests that regulatory mechanism of protein thermal stabilization has entropic nature.

Reply to “Comment on Aromatic‐Backbone Interactions in Model α‐Helical Peptides”

AbstractIn response to Van Mourik's comments on our paper (J Comput Chem 2007, 28, 1208.) we present an extended version of our rotation method. We also prove that intramolecular interaction energies as well the basis set superposition errors calculated with our rotation method are comparable with those obtained by the counterpoise method of Boys and Bernardi (Mol Phys 1970, 19, 533). In intramolecular interaction energy calculations, if the interacting groups are in proximity, our rotation method is recommended to avoid artificial interactions, which can be induced by fragmentation. © 2007 Wiley Periodicals, Inc.J Comput Chem, 2008

Driving Energies of Hydrogen Scrambling Motions in CH5+

A comprehensive quantum chemistry study with natural bond orbital analysis is performed to reveal the intrinsic properties of the floppy potential energy surface of the smallest methonium ion CH5+. In contrast to the low-energy barriers of Cs(I)-->Cs(II)-->Cs(I) and Cs(I)-->C2v-->Cs(I) that correspond to the H2 rotation and H-flip motions, the remarkably larger intramolecular interaction energies are the driving power to mimic the hydrogen scrambling in CH5+. As for the H2 rotation and H-flip motions, the hyperconjugative and electrostatic interactions compete strongly. They together with other interactions compensate for each other and lead to the floppy potential energy surface.