Dimerization Energies Research Articles

Homo- and heteromeric interaction strengths of the synergistic antimicrobial peptides PGLa and magainin 2 in membranes.

PGLa and magainin 2 (MAG2) are amphiphilic α-helical frog peptides with synergistic antimicrobial activity. In vesicle leakage assays we observed the strongest synergy for equimolar mixtures of PGLa and MAG2. This result was consistent with solid-state (15)N-NMR data on the helix alignment in model membranes. The Hill coefficients determined from the vesicle leakage data showed that the heterodimeric (PGLa-MAG2) interactions were stronger than the homodimeric (PGLa-PGLa and MAG2-MAG2) interactions. This result was also reflected in the free energy of dimerization determined from oriented circular dichroism and quantitative solid-state (19)F-NMR analysis.

1,3,5-Triazapentadienes by Nucleophilic Addition to 1,3- and 1,4-Dinitriles-Sterically Constrained Examples by Incorporation into Cyclic Peripheries: Synthesis, Aggregation, and Photophysical Properties.

1,3,5-Triazapentadienes usually show U- or twisted S-shaped conformations along the N-C-N-C-N skeleton due to dominating n/π* interactions. If, however, the 1,3,5-triazapentadiene unit is part of a ring, its W conformation might be restricted to the plane. Here, we describe the synthesis of 13 new 1,3,5-triazapentadienes 10-12, which are sterically restrained by incorporation into six- or seven-membered ring systems, by addition of a lithiated primary amine or hydrazine 5 to a dinitrile 7, 8, or 9 with the two cyano groups in 1,3 or 1,4 distance. These novel compounds show very strong tendency for aggregation due to hydrogen bonding, especially to form homodimers as seen from X-ray data in the solid state. Additional hydrogen bonding generates also linear chains in the crystal. Several of the new compounds show fluorescence in solution. Quantum chemical DFT calculations were used for evaluation of the dimerization energies and for interpretation of the photophysical properties.

Energetics and Predissociation Dynamics of Small Water, HCl, and Mixed HCl-Water Clusters.

This Review summarizes recent research on vibrational predissociation (VP) of hydrogen-bonded clusters. Specifically, the focus is on breaking of hydrogen bonds following excitation of an intramolecular vibration of the cluster. VP of the water dimer and trimer, HCl clusters, and mixed HCl-water clusters are the major topics, but related work on hydrogen halide dimers and trimers, ammonia clusters, and mixed dimers with polyatomic units are reviewed for completion and comparison. The theoretical focus is on generating accurate potential energy surfaces (PESs) that can be used in detailed dynamical calculations, mainly using the quasiclassical trajectory approach. These PESs have to extend from the region describing large amplitude motion around the minimum to regions where fragments are formed. The experimental methodology exploits velocity map imaging to generate pair-correlated product translational energy distributions from which accurate bond dissociation energies of dimers and trimers and energy disposal in fragments are obtained. The excellent agreement between theory and experiment on bond dissociation energies, energy disposal in fragments, and the contributions of cooperativity demonstrates that it is now possible, with state-of-the-art experimental and theoretical methods, to make accurate predictions about dynamical and energetic properties of dissociating clusters.

Evaluating Free Energies of Dimerization of Short Polyglutamine Peptides with Molecular Dynamics Simulations

Huntington's disease is a member of a group of neurodegenerative diseases called polyglutamine diseases, which are characterized by mutations that cause elongated polyglutamine repeats in proteins. Mutated proteins misfold and aggregate into amyloid-like fibrils in the neuron. Experimental techniques are used to analyze the structure of polyglutamine systems, but these methods lack the sensitivity to reveal the behavior of individual peptides on the atomic scale. For this reason, computer simulations are used to fully characterize the structure, dynamics, and energetics of these systems. In the field, short polyglutamine peptides, Q<30, are commonly used as models for study due to their simple sequence and the fact that they form fibrils similar to longer polypeptides. In previous research, we successfully used metadynamics MD simulations to identify low energy structures for the peptide D2Q10K2. Stable -hairpin, PPII-rich, and collapsed random coil structures populate this peptide's conformational free energy landscape. The process by which D2Q10K2 polypeptides dimerization, and subsequently polymerize, into aggregates is unknown. Elucidating this process will shed light on the aggregation scheme of polyglutamine peptides and will also aid in the study of other amyloidoses. In This work, we sought to investigate the free energy and conformation of D2Q10K2 dimerization, designing simulations based on what we know about the monomeric structure of these peptides. Utilizing adaptive biasing force and umbrella sampling MD simulations, we calculated the potential of mean force (PMF) of dimerization for various conformations of monomer. -hairpin structures have been proposed in multiple studies as the nucleating unit for fibril formation. We will use these simulations to test this hypothesis; results from these simulations will be presented.

Stripping the CLC-ec1 Dimerization Interface: An Investigation into the Role of Van Der Waals Interactions in Membrane Protein Assembly

What drives membrane proteins to fold and oligomerize in lipid bilayers? One possibility is that protein-protein interactions stabilize the assembled state. In membrane proteins, interfaces are typically lined by non-polar residues offering weak van der Waals interactions (VDW), yet a large network of these might confer strong stability. To investigate the role of side-chain VDW interactions on the free energy of membrane protein complex formation, we have made a library of mutations on the dimerization interface of the CLC-ec1 Cl-/H+ antiporter - a model system that we have developed to measure equilibrium dimerization in lipid bilayers. The interface is comprised of four alpha-helices lined by non-polar residues: I - F219, I220, I223, I227; H - L194, I197, I198, I201; P - L406, I409, I410, L413; Q - I422A, L423A, I426A, I430A, I434A. We systematically mutated each helix surface to alanine (all-ALA), stripping the interface of its VDW interactions. In all cases the protein expresses, is stable and upon reconstitution in membranes, shows Cl- transport activity comparable to wild-type CLC-ec1. We ran gel-filtration chromatography over the course of one week to screen the stoichiometry of the protein in detergent. All-ALA helix I, P & Q are stable dimers, however all-ALA helix H showed shifts to monomer directly after purification. Furthermore, single-mutant L194A was sufficient to shift the protein to a monomer-dimer mixture. Because helix H interacts with helix P, and all-ALA helix P is still dimeric, these results suggest that dimer stability cannot be explained by VDW interactions alone, at least in detergent. We are currently measuring the change in free energy of CLC-ec1 dimerization with these subtractive mutations to quantify the role of VDW interactions in membrane protein assembly.

Energy transfer in structured and unstructured environments: Master equations beyond the Born-Markov approximations.

We explore excitonic energy transfer dynamics in a molecular dimer system coupled to both structured and unstructured oscillator environments. By extending the reaction coordinate master equation technique developed by Iles-Smith et al. [Phys. Rev. A 90, 032114 (2014)], we go beyond the commonly used Born-Markov approximations to incorporate system-environment correlations and the resultant non-Markovian dynamical effects. We obtain energy transfer dynamics for both underdamped and overdamped oscillator environments that are in perfect agreement with the numerical hierarchical equations of motion over a wide range of parameters. Furthermore, we show that the Zusman equations, which may be obtained in a semiclassical limit of the reaction coordinate model, are often incapable of describing the correct dynamical behaviour. This demonstrates the necessity of properly accounting for quantum correlations generated between the system and its environment when the Born-Markov approximations no longer hold. Finally, we apply the reaction coordinate formalism to the case of a structured environment comprising of both underdamped (i.e., sharply peaked) and overdamped (broad) components simultaneously. We find that though an enhancement of the dimer energy transfer rate can be obtained when compared to an unstructured environment, its magnitude is rather sensitive to both the dimer-peak resonance conditions and the relative strengths of the underdamped and overdamped contributions.

Role of the Lipid Environment in the Dimerization of Transmembrane Domains of Glycophorin A

An efficient computational approach is developed to quantify the free energy of a spontaneous association of the α-helices of proteins in the membrane environment. The approach is based on the numerical decomposition of the free energy profiles of the transmembrane (TM) helices into components corresponding to protein-protein, protein-lipid, and protein-water interactions. The method was tested for the TM segments of human glycophorin A (GpA) and two mutant forms, Gly83Ala and Thr87Val. It was shown that lipids make a significant negative contribution to the free energy of dimerization, while amino acid residues forming the interface of the helix-helix contact may be unfavorable in terms of free energy. The detailed balance between different energy contributions is highly dependent on the amino acid sequence of the TM protein segment. The results show the dominant role of the environment in the interaction of membrane proteins that is changing our notion of the driving force behind the spontaneous association of TM α-helices. Adequate estimation of the contribution of the water-lipid environment thus becomes an extremely urgent task for a rational design of new molecules targeting bitopic membrane proteins, including receptor tyrosine kinases.

Simultaneous interactions of amphoteric halogen in XY (X = Cl, Br and Y = F, Cl, Br) with C and O atoms of CO2 in ring-shaped CO2·X(Y)·CO2 complexes

Dihalogen molecule XY (X=Cl and Br and Y=F, Cl and Br) can interact with two CO2 and form ring-shaped CO2·X(Y)·CO2 trimers, in which the X atom simultaneously interacts with C atom of one CO2 and O atom of the other CO2. Theoretical calculations show that their optimized geometries and stretching vibrational frequencies are different from the individual (CO2)2, CO2⋯XY and YX⋯CO2 dimers. Their interaction energies are stronger than the sum of the interaction energies of the individual dimers, revealing the cooperativity between the dimers. Their binding distances and interaction strengths are closely associated with the electronegativity of X and Y atoms. Energy decomposition analysis suggests that electrostatic force is the main net contribution to total interaction energy. Quantum theory of atoms in molecules analysis confirms the formation of ring-shaped structures and the cooperativity between the dimers. Molecular electrostatic potential was employed to elucidate the formation mechanisms of ring-shaped trimers.

Efficient yet accurate approximations for ab initio calculations of alcohol cluster thermochemistry.

We have calculated the binding enthalpies and entropies of gas phase alcohol clusters from ethanol to 1-decanol. In addition to the monomers, we have investigated dimers, tetramers, and pentamers. Geometries have been obtained at the B3LYP/TZVP level and single point energy calculations have been performed with the Resolution of the Identity-MP2 (RIMP2) method and basis set limit extrapolation using aug-cc-pVTZ and aug-cc-pVQZ basis sets. Thermochemistry is calculated with decoupled hindered rotor treatment for large amplitude motions. The results show three points: First, it is more accurate to transfer the rigid-rotor harmonic oscillator entropies from propanol to longer alcohols than to compute them with an ultra-fine grid and tight geometry convergence criteria. Second, the computational effort can be reduced considerably by using dimerization energies of longer alcohols at density functional theory (B3LYP) level plus a RIMP2 correction obtained from 1-propanol. This approximation yields results almost with the same accuracy as RIMP2 - both methods differ for 1-decanol only 0.4 kJ/mol. Third, the entropy of dimerization including the hindered rotation contribution is converged at 1-propanol with respect to chain length. This allows for a transfer of hindered rotation contributions from smaller alcohols to longer ones which reduces the required computational and man power considerably.

Free energy of helical transmembrane peptide dimerization in OPLS-AA/Berger force field simulations: inaccuracy and implications for partner-specific Lennard-Jones parameters between peptides and lipids

Interactions between transmembrane (TM) peptides are important in biophysical chemistry, but there are few studies assessing atomistic simulation parameters concerning the energetics of interactions of TM helical peptides. Our potential of mean force analysis using OPLS-AA protein/Berger lipid force fields (FFs) shows that the dimerisation energy of (AALALAA)3 helical peptides in the dioleoylphosphatidylcholine bilayer is −4.4 kJ/mol, which was much smaller than the reported experimental value (−12.7 kJ/mol), thus calling for improvement of parameters of the combined FFs. As each of the FFs has been independently developed, we then tested the effects of downscaling the Lennard-Jones (LJ) energy terms between the OPLS-AA atoms and Berger lipid atoms, preserving the parameters within each FF. A 0.9-fold rescaling of the LJ energies was found to render the dimerisation energy close to the experimental value. Solvation of backbone atoms as well as side chain atoms in lipids is crucial for the TM helix interaction. In similar analyses, GROMOS 53A6 FF exhibited as weak dimerisation propensity (~−5.2 kJ/mol) as OPLS-AA/Berger, but CHARMM36 showed relatively accurate propensity (~−9.9 kJ/mol). Challenges and strategies in rendering the TM interaction energy realistic within the framework of current FFs are discussed.

Feasibility of Ionization-Mediated Pathway for Ultraviolet-Induced Melanin Damage.

Melanin is the pigment found in human skin that is responsible for both photoprotection and photodamage. Recently there have been reports that greater photodamage of DNA occurs when cells containing melanin are irradiated with ultraviolet (UV) radiation, thus suggesting that the photoproducts of melanin cause DNA damage. Photoionization processes have also been implicated in the photodegradation of melanin. However, not much is known about the oxidation potential of melanin and its monomers. In this work we calculate the ionization energies of monomers, dimers, and few oligomers of eumelanin to estimate the threshold energy required for the ionization of eumelanin. We find that this threshold is within the UV-B region for eumelanin. We also look at the charge and spin distributions of the various ionized states of the monomers that are formed to understand which of the ionization channels might favor monomerization from a covalent dimer.

Encapsulation of monomers, homodimers and heterodimers of amides and carboxylic acids in three non-covalent assemblies

A structural study has been carried out involving geometry optimization of different capsules and encapsulated complexes of single monomers, homodimers and heterodimers of benzoic acid and benzamide and substituted dimers, as well as hydrogen-bonded networks of benzamide addressing experimental observation, where cages offering similar cavities but made up of slightly different cavitands result in strikingly different dimer distributions. This is attributed, according to the present results, mainly to the fact that the two cages have different formation energy and different dimer encapsulation energy. The generation of hydrogen-bonded networks of the amide in solution acts competitively to encapsulation. In addition, the trends of the different quantities associated with encapsulation such as dimerization energy, % dimer distribution and encapsulation energies, as the size of the dimers is increased, are examined. Furthermore, the efficacy of the ONIOM(DFT or MP2 and CCSD:PM6) method with respect to the calculation of % distribution of encapsulated dimers in limited cavities is studied. The results show that when the interaction of the guests with the cage is significant, the ONIOM % distributions do not agree with the experimental finding, as full DFT does, due to PM6 method, where the use of semi-empirical PM6 method changes the ordering of the low in energy encapsulated complexes.

Theoretical and Computational Modeling of Dimerization Energy for the C6n2H•6n–1 Radicals of the Polycyclic Aromatic Hydrocarbons (PAHs) Homologue Serie

Theoretical and Computational Modeling of Dimerization Energy for the C<i>_6<i>n</i>2</i>H^•_{<i>6<i>n</i></i>–1} Radicals of the Polycyclic Aromatic Hydrocarbons (PAHs) Homologue Serie

Quantitative analysis of intermolecular interactions in orthorhombic rubrene.

Rubrene is one of the most studied organic semiconductors to date due to its high charge carrier mobility which makes it a potentially applicable compound in modern electronic devices. Previous electronic device characterizations and first principles theoretical calculations assigned the semiconducting properties of rubrene to the presence of a large overlap of the extended π-conjugated core between molecules. We present here the electron density distribution in rubrene at 20 K and at 100 K obtained using a combination of high-resolution X-ray and neutron diffraction data. The topology of the electron density and energies of intermolecular interactions are studied quantitatively. Specifically, the presence of Cπ⋯Cπ interactions between neighbouring tetracene backbones of the rubrene molecules is experimentally confirmed from a topological analysis of the electron density, Non-Covalent Interaction (NCI) analysis and the calculated interaction energy of molecular dimers. A significant contribution to the lattice energy of the crystal is provided by H-H interactions. The electron density features of H-H bonding, and the interaction energy of molecular dimers connected by H-H interaction clearly demonstrate an importance of these weak interactions in the stabilization of the crystal structure. The quantitative nature of the intermolecular interactions is virtually unchanged between 20 K and 100 K suggesting that any changes in carrier transport at these low temperatures would have a different origin. The obtained experimental results are further supported by theoretical calculations.

Assessment of Empirical Models versus High-Accuracy Ab Initio Methods for Nucleobase Stacking: Evaluating the Importance of Charge Penetration.

Molecular mechanics (MM) force field models have been demonstrated to have difficulty reproducing certain potential energy surfaces of π-stacked complexes. Here, we examine the performance of the AMBER and CHARMM models relative to high-quality ab initio data across systematic helical parameter scans and typical B-DNA geometries for π-stacking energies of nucleobase dimers. These force fields perform best for typical B-DNA geometries (mean absolute error < 1 kcal mol(-1)), whereas errors typically approach ∼2 kcal mol(-1) for broader potential scans, with maximum errors > 10 kcal mol(-1) relative to high-quality ab initio reference interaction energies. The adequate performance of MM models near minimum energy structures is accomplished through cancellation of errors in various energy terms, whereas large errors at short intermolecular distances are caused by large MM electrostatics errors due to a lack of explicit terms modeling charge penetration effects.

Dimers of Nineteen-Electron Sandwich Compounds: An Electrochemical Study of the Kinetics of Their Formation

Rate constants for the dimerization of FeCp*C6H6, RuCp*mes, RhCp2, RhCp*Cp, and IrCp*Cp (Cp* = pentamethylcyclopentadienyl; mes = 1,3,5-trimethylbenzene; Cp = cyclopentadienyl) have been investigated by cyclic voltammetry. Rates increased in the order FeCp*C6H6 ≪ RhCp*Cp ∼ RhCp2 < RuCp*mes and IrCp*Cp. The difference in rates between the Rh compounds and the Ru and Ir species is consistent with the thermodynamic driving forces for dimerization estimated from DFT calculations. However, the sluggish dimerization of FeCp*C6H6 cannot be rationalized with purely thermodynamic considerations and may be attributable to the very different spin-density distribution in this species. On the basis of the activation parameters for dimerization, determined by variable temperature cyclic voltammetry, and those previously determined for dissociation of the corresponding dimer, the free energy of dimerization for the RhCp*Cp monomer was estimated to be −43 kJ mol–1, and the effective redox potential for the RhCp*Cp+/ 0.5(...

Directionality of intermolecular C–F···F–C interactions in crystals: experimental and theoretical charge density study

Bonding intermolecular F···F interactions were analyzed in crystal of a fluorinated benzene derivative using topological analysis of experimental charge density distribution. It was found that the values of electron density and potential energy density in bond critical points of the F···F interactions in crystal depended on the distance between the fluorine atoms, rather than on the corresponding C–F···F angles. The directionality of these F···F interactions was demonstrated by DFT-D and MP2 calculations for model hexafluorobenzene dimers. Possible discrepancies between dimerization energies computed by ab initio methods and via empirical correlations are discussed.

Thermochemistry of HO2 + HO2 → H2O4: Does HO2 Dimerization Affect Laboratory Studies?

Self-reaction is an important sink for the hydroperoxy radical (HO2) in the atmosphere. It has been suggested (Denis, P. A.; Ornellas, F. R. J. Phys. Chem. A, 2009, 113 (2), 499-506) that the minor product hydrogen tetroxide (HO4H) may act as a reservoir of HO2. Here, we compute the thermochemistry of HO2 self-reactions to determine if either HO4H or the cyclic hydrogen-bound dimer (HO2)2 can act as reservoirs. We computed electronic energies using coupled-cluster calculations in the complete basis set limit, CCSD(T)/CBS[45]//CCSD(T)/cc-pVTZ. Our model chemistry includes corrections for vibrational anharmonicity in the zero-point energy and vibrational partition functions, core-valence correlation, scalar relativistic effects, diagonal Born-Oppenheimer, spin-orbit splitting, and higher-order corrections. We compute the Gibbs energy of dimerization to be (-20.1 ± 1.6) kJ/mol at 298.15 K (2σ uncertainty), and (-32.3 ± 1.5) kJ/mol at 220 K. For atmospherically relevant [HO2] = 10(8) molecules per cm(3), our thermochemistry indicates that dimerization will be negligible, and thus H2O4 species are atmospherically unimportant. Under conditions used in laboratory experiments ([HO2] > 10(12) molecules per cm(3), 220 K), H2O4 formation may be significant. We compute two absorption spectra that could be used for laboratory detection of HO4H: the OH stretch overtone (near-IR) and electronic (UV) spectra.

Positive and Negative Contributions in the Solvation Enthalpy due to Specific Interactions in Binary Mixtures of C1-C4 n-Alkanols and Chloroform with Butan-2-one.

In the paper, results of calorimetric measurements, IR spectra, and calculated ab initio stabilization energies of dimers are reported for binary systems butan-2-one + (methanol, ethanol, propan-1-ol, butan-1-ol, and chloroform). Changes in the total enthalpy of specific interactions due to dissolution of butan-2-one in the alcohols, calculated using equations derived in previous works, are positive. That results from the endothermic breaking of the O-H···O-H bonds not completely compensated by the exothermic effects of formation of the O-H···O═C ones. Moreover, the concentration of nonbonded molecules of butan-2-one is significant even in dilute solutions, as is evidenced by the shape of the C═O stretching vibrations band in the IR spectra. Apart from that, the spectra do not confirm 1:2 complexes in spite of two lone electron pairs in the carbonyl group of butan-2-one capable of forming the hydrogen bonds. The changes in enthalpy of specific interactions are negative for dilute solutions of alcohols and chloroform in butan-2-one and of butan-2-one in chloroform, because no hydrogen bonds occur in pure butan-2-one. The experimental results are positively correlated with the enthalpies estimated from the ab initio energies using a simple "chemical reaction" approach.

Coupling of Zinc-Binding and Secondary Structure in Nonfibrillar Aβ40 Peptide Oligomerization.

Nonfibrillar neurotoxic amyloid β (Aβ) oligomer structures are typically rich in β-sheets, which could be promoted by metal ions like Zn(2+). Here, using molecular dynamics (MD) simulations, we systematically examined combinations of Aβ40 peptide conformations and Zn(2+) binding modes to probe the effects of secondary structure on Aβ dimerization energies and kinetics. We found that random conformations do not contribute to dimerization either thermodynamically or kinetically. Zn(2+) couples with preformed secondary structures (α-helix and β-hairpin) to speed dimerization and stabilize the resulting dimer. Partial α-helices increase the dimerization speed, and dimers with α-helix rich conformations have the lowest energy. When Zn(2+) coordinates with residues D1, H6, H13, and H14, Aβ40 β-hairpin monomers have the fastest dimerization speed. Dimers with experimentally observed zinc coordination (E11, H6, H13, and H14) form with slower rate but have lower energy. Zn(2+) cannot stabilize fibril-like β-arch dimers. However, Zn(2+)-bound β-arch tetramers have the lowest energy. Collectively, zinc-stabilized β-hairpin oligomers could be important in the nucleation-polymerization of cross-β structures. Our results are consistent with experimental findings that α-helix to β-structural transition should accompany Aβ aggregation in the presence of zinc ions and that Zn(2+) stabilizes nonfibrillar Aβ oligomers and, thus, inhibits formation of less toxic Aβ fibrils.