Intramolecular Interaction Energies Research Articles

A new Thiadiazole-triazine derivative: Structural investigation, DFT studies, ADME-T analysis and SARS-CoV-2 activity by docking simulation

The present work involves the synthesis of thiadiazole-triazine derivative 7-[2-(4-bromophenyl)ethenyl]-3‑tert‑butyl‑4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-one (TCA3) and spectroscopic characterization is done using NMR and X-ray diffraction techniques. The single crystal X-ray diffraction study unravels the 3D structure of the compound TCA3. The compound crystallizes in the monoclinic crystal system with the space group P21/c. The crystal structure analysis revealed that various CH…O, CH…N, and CH…Br interactions are responsible for crystal packing. Furthermore, Hirshfeld surface analysis has been performed to visualize and analyze the intermolecular interactions observed in the crystal structure. Energy framework analysis was used to explore the molecular architecture in the crystal, and to calculate the molecular interaction energies of the compound TCA3. DFT calculations have also been carried out to explore the various physicochemical properties of the compound like HOMO-LUMO energy gap of the molecule, reactive sites present in the molecule using MEP analysis. The energy gap of the molecule is found to be 4.592 eV. Also, to know the strength and nature of intramolecular interaction energy using RDG analysis. Finally, the potential inhibitory activity of the titled compounds and their drug-likeness are demonstrated by ADME-T calculations. Further, The structure-activity relationships established through molecular docking studies showed that the compound TCA3 strongly binds to the receptors Mpro (-8.2 Kcal/mol) which confirm its inhibition activity against COVID-19.

Real-time structural signatures of protein allostery by electrically- and mechanically-coupled sensing

Accurate detection and identification of conformational evolutions are essential to describe the micro-structural mechanisms of protein allostery. Here we establish an approach by integrating nanopore sensing technique with atomic force microscopy, based on molecular dynamics simulations. A theoretical method is further developed to real-time estimate the low-resolution structures of those evolved conformations. Tests for the forced allostery of αXβ2 integrin, a typical protein with multiple functional states, demonstrate that the spheroidal shape identifiers of those intermediate conformers present sufficient sensitivity to resolve two allosteric patterns of αXβ2 from bent-down to stand-up states under the nanopore confinement. The strong steric confinement from the nanopore restricts the geometric displacements of key domains in conformational extension dynamics, thereby increasing the intramolecular interaction energy barrier to be overcome for standing. Prolongation of the neck-shoulder region of αXβ2 and opening at the thigh-calf joint form a competitive compensation for the stretched height, resulting in two tendentious allosteric patterns under various confined diameters and steered speeds. Thus, this study proposes a new method to real-time visualize the conformational dynamics during protein allostery, favoring to depict structural characteristics for the conformations of those transient states and evaluate the impacts of the nanopore confinement on protein allostery.

What are the minimal folding seeds in proteins? Experimental and theoretical assessment of secondary structure propensities of small peptide fragments.

Certain peptide sequences, some of them as short as amino acid triplets, are significantly overpopulated in specific secondary structure motifs in folded protein structures. For example, 74% of the EAM triplet is found in α-helices, and only 3% occurs in the extended parts of proteins (typically β-sheets). In contrast, other triplets (such as VIV and IYI) appear almost exclusively in extended parts (79% and 69%, respectively). In order to determine whether such preferences are structurally encoded in a particular peptide fragment or appear only at the level of a complex protein structure, NMR, VCD, and ECD experiments were carried out on selected tripeptides: EAM (denoted as pro-'α-helical' in proteins), KAM(α), ALA(α), DIC(α), EKF(α), IYI(pro-β-sheet or more generally, pro-extended), and VIV(β), and the reference α-helical CATWEAMEKCK undecapeptide. The experimental data were in very good agreement with extensive quantum mechanical conformational sampling. Altogether, we clearly showed that the pro-helical vs. pro-extended propensities start to emerge already at the level of tripeptides and can be fully developed at longer sequences. We postulate that certain short peptide sequences can be considered minimal "folding seeds". Admittedly, the inherent secondary structure propensity can be overruled by the large intramolecular interaction energies within the folded and compact protein structures. Still, the correlation of experimental and computational data presented herein suggests that the secondary structure propensity should be considered as one of the key factors that may lead to understanding the underlying physico-chemical principles of protein structure and folding from the first principles.

Intramolecular interaction between sidechains in intact Trp-cage miniprotein(TC5b)

Intramolecular interaction energies of sidechains in the intact TC5b are individually computed using density fitted 2nd order Moller-Plesset perturbation theory with aug-cc-pVTZ basis set. Large intramolecular interaction energies are observed in between residue lysine(8), aspartate(9), and arginine(16). Strong attractive interaction is also observed between terminal residues. In general, the interaction energies between sidechains without the influence of solvent molecules are relatively small if the pair does not have charges. The sum of 2-body interactions between sidechains in residues1-10 and residues 11–20 are found to be attractive, consistent with the fact TC5b is known to fold at physiological pH. This is largely due to attractive interactions between the charged residues arginine(16) and aspartate(9).

Understanding the Role of Intramolecular Ion-Pair Interactions in Conformational Stability Using an Ab Initio Thermodynamic Cycle

Intramolecular ion-pair interactions yield shape and functionality to many molecules. With proper orientation, these interactions overcome steric factors and are responsible for the compact structures of several peptides. In this study, we present a thermodynamic cycle based on isoelectronic and alchemical mutation to estimate the intramolecular ion-pair interaction energy. We determine these energies for 26 benchmark molecules with common ion-pair combinations and compare them with results obtained using intramolecular symmetry-adapted perturbation theory. For systems with long linkers, the ion-pair energies evaluated using both approaches deviate by less than 2.5% in the vacuum phase. The thermodynamic cycle based on density functional theory facilitates calculations of salt-bridge interactions in model tripeptides with continuum/microsolvation modeling and four large peptides: 1EJG (crambin), 1BDK (bradykinin), 1L2Y (a mini-protein with a tryptophan cage), and 1SCO (a toxin from the scorpion venom).

Structural and theoretical insights towards the understanding of the effect on the conformation of ligand by complexation process

The ligand and the palladium complex were synthesized and characterized by the single crystal X-ray diffraction method. The Hirshfeld surface analysis quantified the intermolecular interactions stabilizing the crystal packing in both compounds. DFT (density functional theory) calculations were used to optimize the geometric structures and calculate the electronic properties of the synthesized compounds. The ligand and complex's electronic structure and UV-Vis spectrum are interpreted by DFT and TD-DFT (time dependent-density functional theory) calculations. The NBO (natural bond orbital) analysis was employed to study the origin and nature of the hyperconjugation interactions. The intramolecular interaction energies associated with different topologies were calculated using the QTAIM (Quantum Theory of Atoms in Molecules), and the non-covalent interactions revealed the type and nature of the interactions exhibited by the compound. The structural and theoretical analysis revealed the change in the properties of the ligand due to the complexation process.

Methoxyl-substituted phosphine ligand properties and a case study of formation adducts to indium(III) bromide by DFT calculations

Six bulky triphenylphosphine ligands containing substituted methoxyl groups (tris(2,4,6-trimethoxyphenyl)phosphine (TMP), tris(2,6-dimethoxyphenyl)phosphine (TDP), tris(o-methoxyphenyl)phosphine (o-Anis3P), tris(p-methoxyphenyl)phosphine (p-Anis3P), tris(m-methoxyphenyl)phosphine (m-Anis3P) and triphenylphosphine (PPh3)) were studied by DFT (density functional theory) calculations and experimental solution/solid-state 31P NMR spectroscopy. The basicity and binding ability of these substituted ligands, proven by comparison of structural data with DFT-predicted data, are in the order TMP > TDP > o-Anis3P > p-Anis3P > m-Anis3P > PPh3. Molecular structures for InBr3 with bulky ligands (TMP, TDP, o-Anis3P, p-Anis3P, m-Anis3P and PPh3) were calculated using DFT. P-In bond distances generated from these six optimized molecular structures and the calculated intramolecular interaction energies are in agreement with the ligand properties, with strong donation ability for those with the short bond distance; the In-P bond distance from shortest to longest follows a similar trend as predicted by DFT calculations. DFT calculations for these adducts show that methoxyl substitution to triphenylphosphine (PPh3) ligands contributed to its electron donor ability resulting in lower P-In bond distances with relatively large bond interaction energies.

Spatial organization of hydrophobic and charged residues affects protein thermal stability and binding affinity

What are the molecular determinants of protein–protein binding affinity and whether they are similar to those regulating fold stability are two major questions of molecular biology, whose answers bring important implications both from a theoretical and applicative point of view. Here, we analyze chemical and physical features on a large dataset of protein–protein complexes with reliable experimental binding affinity data and compare them with a set of monomeric proteins for which melting temperature data was available. In particular, we probed the spatial organization of protein (1) intramolecular and intermolecular interaction energies among residues, (2) amino acidic composition, and (3) their hydropathy features. Analyzing the interaction energies, we found that strong Coulombic interactions are preferentially associated with a high protein thermal stability, while strong intermolecular van der Waals energies correlate with stronger protein–protein binding affinity. Statistical analysis of amino acids abundances, exposed to the molecular surface and/or in interaction with the molecular partner, confirmed that hydrophobic residues present on the protein surfaces are preferentially located in the binding regions, while charged residues behave oppositely. Leveraging on the important role of van der Waals interface interactions in binding affinity, we focused on the molecular surfaces in the binding regions and evaluated their shape complementarity, decomposing the molecular patches in the 2D Zernike basis. For the first time, we quantified the correlation between local shape complementarity and binding affinity via the Zernike formalism. In addition, considering the solvent interactions via the residue hydropathy, we found that the hydrophobicity of the binding regions dictates their shape complementary as much as the correlation between van der Waals energy and binding affinity. In turn, these relationships pave the way to the fast and accurate prediction and design of optimal binding regions as the 2D Zernike formalism allows a rapid and superposition-free comparison between possible binding surfaces.

Controlling the Dual-Emission Character of Aryl-Modified o-Carboranes by Intramolecular CH⋅⋅⋅O Interaction Sites.

It is still challenging to realize a dual-emission system, in which two luminescent bands simultaneously appear by photoexcitation, in solid with organic dyes due to the difficulty in regulation of electronic properties in the excited state and concentration quenching. o-Carborane is known to be a versatile platform for constructing solid-state emitters since the sphere boron cluster is favorable for suppressing intermolecular interactions and subsequently concentration quenching. Here, we show solid-state dual-emissive o-carborane derivatives. We prepared 4 types of o-carborane derivatives and found dual-emission behaviors both in solution and solid states. By regulating the rotation at the o-carborane unit with the intramolecular Ccage H⋅⋅⋅O interaction, the dual-emission intensity ratios were changed. Finally, it was demonstrated that the overall photoluminescence spectra can be estimated using the binding energy of intramolecular interactions.

Regio and stereochemical probes of iodine interactions in diiodocyclododecanes

AbstractCyclododecane preferentially adopts a square‐like geometry, giving rise to corner and edge methylene (CH2) groups, whose hydrogens assume different orientations. In edge CH2 groups, hydrogens can be inward‐ (endo) and outward‐looking (exo) the ring. Herein, we have quantum‐chemically studied the replacement of two hydrogens in cyclododecane with iodines at the relative positions 1,4, 1,5, 1,6, and 1,7. Intramolecular interactions are only slightly unfavorable in 1,7‐diiodocyclododecane containing the organic iodines in the edge/endo positions, less than expected from steric considerations. This behavior was discussed in terms of transannular interactions, and a numerical estimation for the magnitude of the intramolecular interaction energy has been performed based on an isodesmic reaction scheme and by natural energy decomposition analysis. 1,5‐Diiodocyclododecane with both edge iodines in the endo orientation (occupying opposite faces of the ring) is strongly favored (by ca. 2.0 kcal mol−1) compared to the respective monosubstituted counterparts, due to highly stabilizing hyperconjugative interactions. Although halogen bonding involving anionic species is widely known, we show that organic halogens, in particular iodine, can be useful for stereochemical control in macrocycles.

A REP-FAMSEC Method as a Tool in Explaining Reaction Mechanisms: A Nucleophilic Substitution of 2-Phenylquinoxaline as a DFT Case Study.

In search for the cause leading to low reaction yields, each step along the reaction energy profile computed for the assumed oxidative nucleophilic substitution of hydrogen (ONSH) reaction between 2-phenylquinoxaline and lithium phenylacetylide was modelled computationally. Intermolecular and intramolecular interaction energies and their changes between consecutive steps of ONSH were quantified for molecular fragments playing leading roles in driving the reaction to completion. This revealed that the two reactants have a strong affinity for each other, driven by the strong attractive interactions between Li and two N-atoms, leading to four possible reaction pathways (RP-C2, RP-C3, RP-C5, and RP-C10). Four comparable in energy and stabilizing molecular system adducts were formed, each well prepared for the subsequent formation of a C–C bond at either one of the four identified sites. However, as the reaction proceeded through the TS to form the intermediates (5a–d), very high energy barriers were observed for RP-C5 and RP-C10. The data obtained at the nucleophilic addition stage indicated that RP-C3 was both kinetically and thermodynamically favored over RP-C2. However, the energy barriers observed at this stage were very comparable for both RPs, indicating that they both can progress to form intermediates 5a and 5b. Interestingly, the phenyl substituent (Ph1) on the quinoxaline guided the nucleophile towards both RP-C2 and RP-C3, indicating that the preferred RP cannot be attributed to the steric hindrance caused by Ph1. Upon the introduction of H2O to the system, both RPs were nearly spontaneous towards their respective hydrolysis products (8a and 8b), although only 8b can proceed to the final oxidation stage of the ONSH reaction mechanism. The results suggest that RP-C2 competes with RP-C3, which may lead to a possible mixture of their respective products. Furthermore, an alternative, viable, and irreversible reaction path was discovered for the RP-C2 that might lead to substantial waste. Finally, the modified experimental protocol is suggested to increase the yield of the desired product.

ПРОСТРАНСТВЕННАЯ СТРУКТУРА НЕЙРОПЕПТИДА MET-CALLATOSTATIN

In work by the method of molecular mechanics in approximation of atom-atom potential functions is studied the spatial structure and conformational properties of the molecules from allatostatin family, got the name of Met-callatostatin. The researches were based on minimizing of the energy of intramolecular interactions (non-bonded, electrostatic, torsion) in the vicinity of the internal rotation angles corresponding to all combinations of stable conformations of monopeptide residues forming a molecule. There determined ten energetically stable conformations of molecules, implemented under the conditions of implicitly given aqueous environment, the relative conformational energy of which varies in the range of 0-10 kcal / mol. It was shown that the system of hydrogen bonds, despite a small contribution to the total energy of the molecule is essential for the preservation of a stable structure and restriction of Met-callatostatin. Key words: neuropeptides, structure, conformational analysis, peptides, by molecular mechanics

A Critical Overview of Current Theoretical Methods of Estimating the Energy of Intramolecular Interactions.

This article is probably the first such comprehensive review of theoretical methods for estimating the energy of intramolecular hydrogen bonds or other interactions that are frequently the subject of scientific research. Rather than on a plethora of numerical data, the main focus is on discussing the theoretical rationale of each method. Additionally, attention is paid to the fact that it is very often possible to use several variants of a particular method. Both of the methods themselves and their variants often give wide ranges of the obtained estimates. Attention is drawn to the fact that the applicability of a particular method may be significantly limited by various factors that disturb the reliability of the estimation, such as considerable structural changes or new important interactions in the reference system.

What Is the Main Feature Distinguishing the Through-Space Interactions in Cyclophanes from Their Aliphatic Analogues?

Classical cyclophanes with two benzene rings have been compared with cyclophanes with one benzene ring replaced with an aliphatic part and aliphatic compounds, which are cyclophane analogues. Analysis of geometry, atomic charges, and aromatic and steric energy and investigation of intramolecular noncovalent interactions and charge mobility show that there is no special feature that distinguishes the classical cyclophanes from aliphatic analogues, so the definition of cyclophanes can be extended to other compounds.

Energy of Intramolecular Interactions and Structure of Metallophosphate Polycomplexes with Water Molecules and Nitrogen-Containing Compounds

The interaction energies of fragments of aluminoborophosphate chains with water molecules and nitrogen-containing compounds are calculated using a density functional theory (DFT). The conformational changes of monomer units of aluminophosphate and molecular complexes during the formation of hydrogen bonds are analyzed. The complexation of aluminoborophosphate with various nitrogen-containing compounds, which leads to the displacement of water from the chain surface, is considered, and the thermal effects of complex formation are calculated. The moisture absorption of mixtures of oligomeric aluminoborophosphate with amines was measured upon various ratios of components.

Interplay between Conformational Strain and Intramolecular Interaction in Protein Structures: Which of Them Is Evolutionarily Conserved?

By computing strain energies of peptide fragments within protein structures and their intramolecular interaction energies, we attempt to reveal general biophysical trends behind the secondary structure formation in the context of protein evolution. Our "protein basis set" consisted of 1143 representatives of different folds obtained from curated SCOPe database, and for each member of the set, the strain and intramolecular energy was calculated on the "rolling tripeptide" basis, employing the DFT-D3/COSMO-RS method for the former and the QM-calibrated force field method (MM) for the latter. The calculated data, strain and interactions, were correlated with the conservation of amino acid residues in secondary structure elements and also with the level of the residue burial within the protein three-dimensional structure. It allowed us to formulate several observations concerning fundamental differences between two main secondary structure motifs: α-helices and β-strands. We have shown that a strong interaction is one of the determining characteristics of the β-sheet formation, at least at the level of tripeptides (and likely penta- or heptapeptides, too), and that the β-strand is a prevailing secondary structure in the strongly-interacting regions of the protein folds conserved by evolution. On the other hand, low strain was neither proven to be an important physicochemical property conserved by evolution nor does it correlate with the propensity for the α-helix and β-strand. Finally, it has been demonstrated that the strong interaction has a certain level of connection with residue burial; however, we demonstrate that these two characteristics should be rather regarded as two complementary factors. These findings represent an important contribution to understanding protein folding from first principles, which is a complementary approach to ongoing efforts to solve the protein folding problem by knowledge-based approaches and machine-learning.

Long-range dispersion-corrected density functional for noncovalent interactions

Noncovalent interactions are important in determining structures and properties of molecular complexes and biological molecules, and for understanding adsorption processes in chemistry and biological science, and are still challenging to conventional density functional theories. In this work, the recently developed Tao-Mo (TM) meta-GGA (generalized gradient approximation) functional is combined with the D3 scheme of long-range van der Waals (vdW) interaction correction and the parameters of damping function are optimized with the S66[Formula: see text]×[Formula: see text]8 set. The resulting TM-D3 method is applied to the medium-sized molecular set S22 and large size molecular complexes set L7 to calculate intramolecular interaction energies. The TM-D3 method produces the best accuracy for the S22 set with a MAE of 0.2 kcal/mol, improving upon the PBE-D3 (MAE[Formula: see text]=[Formula: see text]0.5 kcal/mol), PBE0-D3 (MAE[Formula: see text]=[Formula: see text]0.5 kcal/mol), TPSS-D3 (MAE[Formula: see text]=[Formula: see text]0.4 kcal/mol), M06L (MAE[Formula: see text]=[Formula: see text]0.8 kcal/mol), and SCAN-D3 (MAE[Formula: see text]=[Formula: see text]0.4 kcal/mol) methods. For the large size set L7, the TM-D3 (MAE[Formula: see text]=[Formula: see text]2.1 kcal/mol) also performs better than the PBE-D3 (MAE[Formula: see text]=[Formula: see text]2.6 kcal/mol), SCAN-D3 (2.5 kcal/mol) and M06L (3.0 kcal/mol), but not accurate than the PBE0-D3 (MAE[Formula: see text]=[Formula: see text]0.8 kcal/mol) and TPSS-D3 (MAE[Formula: see text]=[Formula: see text]1.1 kcal/mol). However, overall, the TM-D3 method performs very well with an error of 2.7% of mean binding of the S22 set and an error of 12.6% of the mean binding of the L7 set for the two typical and important medium and large size molecular complex sets. The success of the dispersion-corrected TM functional benefits from the ability of the plain TM functional to capture the short-range vdW interaction or extend the short-range interaction to the middle range, and the right coupling between the TM and the long-range vdW correction D3 scheme, leading to the improved description of noncovalent interactions.

Formation of Protein Networks between Mucins: Molecular Dynamics Study Based on the Interaction Energy of the System

Molecular dynamics simulations have been performed for a model aqueous solution of mucin. As mucin is a central part of lubricin, a key component of synovial fluid, we investigate its ability to form cross-linked networks. Such network formation could be of major importance for the viscoelastic properties of the soft-matter system and crucial for understanding the lubrication mechanism in articular cartilage. Thus, the inter- and intra-molecular interaction energies between the residues of mucin are analyzed. The results indicate that the mucin concentration significantly impacts its cross-linking behavior. Between 160 g/L and 214 g/L, there seems to be a critical concentration above which crowding begins to alter intermolecular interactions and their energies. This transition is further supported by the mean squared displacement of the molecules. At a high concentration, the system starts to behave subdiffusively due to network development. We also calculate a sample mean squared displacement and p-variation tests to demonstrate how the statistical nature of the dynamics is likewise altered for different concentrations.

Factors Stabilizing β-Sheets in Protein Structures from a Quantum-Chemical Perspective.

Protein folds are determined by the interplay between various (de)stabilizing forces, which can be broadly divided into a local strain of the protein chain and intramolecular interactions. In contrast to the α-helix, the β-sheet secondary protein structure is significantly stabilized by long-range interactions between the individual β-strands. It has been observed that quite diverse amino acid sequences can form a very similar small β-sheet fold, such as in the three-β-strand WW domain. Employing "calibrated" quantum-chemical methods, we show herein on two sequentially diverse examples of the WW domain that the internal strain energy is higher in the β-strands and lower in the loops, while the interaction energy has an opposite trend. Low strain energy computed for peptide sequences in the loop 1 correlates with its postulated early formation in the folding process. The relatively high strain energy within the β-strands (up to 8 kcal mol-1 per amino acid residue) is compensated by even higher intramolecular interaction energy (up to 15 kcal mol-1 per residue). It is shown in a quantitative way that the most conserved residues across the structural family of WW domains have the highest contributions to the intramolecular interaction energy. On the other hand, the residues in the regions with the lowest strain are not conserved. We conclude that the internal interaction energy is the physical quantity tuned by evolution to define the β-sheet protein fold.

Synthesis, crystal structure, vibrational spectra, nonlinear optical property of an organic charge-transfer compound―4-nitrobenzyl isoquinolinium picrate based on DFT calculations

Single crystals of an organic charge-transfer compound, 4-nitrobenzyl isoquinolinium picrate, [4NO2BzIQl][PIC](1), were grown by slow evaporation technique at room temperature. Single crystal XRD and powder XRD studies conform the crystal structure and crystalline nature. In the title compound, the [4NO2BzIQl]+ cations and the [PIC]- anions stack into a columnar structure through π···π and CH···π interactions. The FT-IR and Raman spectra were recorded and analyzed with the aid of density functional theory calculations in order to make a suitable assignment of the observed bands. The simulated spectrum satisfactorily coincides with the experimental UV–visible spectrum. Thermal stability and the major gaseous products of decomposition at 293 °C were examined by TG-DTA-MS technique. The material shows three main emission peaks about 385, 467 and 538 nm upon excitation at 241 nm in solid state at room temperature. The excited state energy from theoretical UV–vis spectra, the total energy of intramolecular interactions and nonlinear optical properties were studied using DFT calculations.