Effective prediction of short hydrogen bonds in proteins via machine learning method

Short hydrogen bonds (SHBs), whose donor and acceptor heteroatoms lie within 2.7 Å, exhibit prominent quantum mechanical characters and are connected to a wide range of essential biomolecular processes. However, exact determination of the geometry and functional roles of SHBs requires a protein to be at atomic resolution. In this work, we analyze 1260 high-resolution peptide and protein structures from the Protein Data Bank and develop a boosting based machine learning model to predict the formation of SHBs between amino acids. This model, which we name as machine learning assisted prediction of short hydrogen bonds (MAPSHB), takes into account 21 structural, chemical and sequence features and their interaction effects and effectively categorizes each hydrogen bond in a protein to a short or normal hydrogen bond. The MAPSHB model reveals that the type of the donor amino acid plays a major role in determining the class of a hydrogen bond and that the side chain Tyr-Asp pair demonstrates a significant probability of forming a SHB. Combining electronic structure calculations and energy decomposition analysis, we elucidate how the interplay of competing intermolecular interactions stabilizes the Tyr-Asp SHBs more than other commonly observed combinations of amino acid side chains. The MAPSHB model, which is freely available on our web server, allows one to accurately and efficiently predict the presence of SHBs given a protein structure with moderate or low resolution and will facilitate the experimental and computational refinement of protein structures.

How electron-deficient Cp ligand facilitates Rh-catalyzed annulations with alkynes

The mechanism and origin of CpX ligand effects on Rh-catalyzed annulations with alkynes were investigated by using DFT calculations and the approach of energy decomposition analysis (EDA). The results reveal...

Identifying the Hot Spot Residues of the SARS-CoV-2 Main Protease Using MM-PBSA and Multiple Force Fields

In this study, we investigated the binding affinities between the main protease of SARS-CoV-2 virus (Mpro) and its various ligands to identify the hot spot residues of the protease. To benchmark the influence of various force fields on hot spot residue identification and binding free energy calculation, we performed MD simulations followed by MM-PBSA analysis with three different force fields: CHARMM36, AMBER99SB, and GROMOS54a7. We performed MD simulations with 100 ns for 11 protein–ligand complexes. From the series of MD simulations and MM-PBSA calculations, it is identified that the MM-PBSA estimations using different force fields are weakly correlated to each other. From a comparison between the force fields, AMBER99SB and GROMOS54a7 results are fairly correlated while CHARMM36 results show weak or almost no correlations with the others. Our results suggest that MM-PBSA analysis results strongly depend on force fields and should be interpreted carefully. Additionally, we identified the hot spot residues of Mpro, which play critical roles in ligand binding through energy decomposition analysis. It is identified that the residues of the S4 subsite of the binding site, N142, M165, and R188, contribute strongly to ligand binding. In addition, the terminal residues, D295, R298, and Q299 are identified to have attractive interactions with ligands via electrostatic and solvation energy. We believe that our findings will help facilitate developing the novel inhibitors of SARS-CoV-2.

Modeling and characterization of exciplexes in photoredox CO2 reduction: Insights from quantum chemistry and fluorescence spectroscopy

Interactions between excited state arenes and amines can lead to the formation of structures with distinct emission behavior. These excited state complexes or exciplexes can reduce the ability of the arene to participate in other reactions, such as CO2 reduction, or increase the likelihood of degradation via Birch reduction. Exciplex geometries are necessary to understand photophysical behavior and probe degradation pathways but are challenging to calculate. We establish a detailed computational protocol for calculation, verification, and characterization of exciplexes. Using fluorescence spectroscopy, we first demonstrate the formation of exciplexes between excited state oligo-(p-phenylene) (OPP), shown to successfully carry out CO2 reduction, and triethylamine (TEA). Time-dependent density functional theory (TDDFT) is employed to optimize the geometries of these exciplexes, which are validated by comparing both emission energies and their solvatochromism with experiment. Excited state energy decomposition analysis confirms the predominant role played by charge transfer interactions in the red-shift of emissions relative to the isolated excited state OPP*. We find that although the exciplex emission frequency depends strongly on solvent dielectric, the extent of charge separation in an exciplex does not. Our results also suggest that the formation of solvent-separated ionic radical states upon complete electron transfer competes with exciplex formation in higher dielectric solvents, thereby leading to reduced exciplex emission intensities in fluorescence experiments.

Computational Chemistry of Compounds with Donor-Acceptor Interactions

<p>Compounds with donor-acceptor interactions find important applications in catalysis, C-H activation, phosphorus activation, selective oxidation and cyclization. Moreover, they are potential candidates for use in the synthesis of materials, polymers and light-harvesting systems. The efficient use of a chemical entity is possible when we know its structural and bonding properties. This computational study is intended for the same by studying in detail the structure and bonding properties of donor-acceptor complexes of heavier main-group metals with cyclophane ligands and some heterobimetallic complexes. Additionally, we explored the fluorescence characteristics of benzanthrone dyes. The first part (i.e. main group metal complexes) involves the exploration of structural features and thermal properties through DFT optimization and then calculating the change in enthalpy of formation for all the possibilities under consideration. For this purpose we selected the last three elements from each of Groups 13, 14 and 15 to explore their different coordination modes with two cyclophane ligands; [2.2.2]paracyclophane and deltaphane. We opted for chlorides of each metal to allow them to coordinate from outside the phenyl rings of the cyclophane cavity and from the top of the cavity. To see the coordination of the metals with the inner core of the selected cyclophanes, we put metal cations in the centre of the cavity and optimized. Subsequently, the bonding properties of these inclusion complexes have been analysed in detail on the basis of Morokuma-Ziegler energy decomposition analysis. Secondly, we investigated the structure and bonding properties of some indium-zinc heterobimetallic compounds through geometry optimization, NBO analysis and quantum theory of atoms in molecules (QTAIM) analysis--also known as Bader's analysis. We propose that the heterobimetallic reactant involves donor-acceptor bond that cleaves as a result of the addition of mesityl azide. The newly formed complex has In-N and Zn-N bonds. In the final part benzanthrone dyes containing intramolecular donor-acceptor interactions, (and hence, undergoing intramolecular charge transfer) were subject to the computational investigation of the mechanism of fluorescence taking place in them. Electronic excitations and the structure of first excited state in each case has been discussed thoroughly based on the time-dependent density functional theory. To check for the non-radiative loss of energy, we also performed calculations for the vertical excitations of the triplet states of all the molecules under study. To get a deeper insight into the intramolecular charge transfer, we performed NTO analysis that gives us information based on different colours in regions of charge accumulation and charge depletion.</p>

Computational Chemistry of Compounds with Donor-Acceptor Interactions

<p>Compounds with donor-acceptor interactions find important applications in catalysis, C-H activation, phosphorus activation, selective oxidation and cyclization. Moreover, they are potential candidates for use in the synthesis of materials, polymers and light-harvesting systems. The efficient use of a chemical entity is possible when we know its structural and bonding properties. This computational study is intended for the same by studying in detail the structure and bonding properties of donor-acceptor complexes of heavier main-group metals with cyclophane ligands and some heterobimetallic complexes. Additionally, we explored the fluorescence characteristics of benzanthrone dyes. The first part (i.e. main group metal complexes) involves the exploration of structural features and thermal properties through DFT optimization and then calculating the change in enthalpy of formation for all the possibilities under consideration. For this purpose we selected the last three elements from each of Groups 13, 14 and 15 to explore their different coordination modes with two cyclophane ligands; [2.2.2]paracyclophane and deltaphane. We opted for chlorides of each metal to allow them to coordinate from outside the phenyl rings of the cyclophane cavity and from the top of the cavity. To see the coordination of the metals with the inner core of the selected cyclophanes, we put metal cations in the centre of the cavity and optimized. Subsequently, the bonding properties of these inclusion complexes have been analysed in detail on the basis of Morokuma-Ziegler energy decomposition analysis. Secondly, we investigated the structure and bonding properties of some indium-zinc heterobimetallic compounds through geometry optimization, NBO analysis and quantum theory of atoms in molecules (QTAIM) analysis--also known as Bader's analysis. We propose that the heterobimetallic reactant involves donor-acceptor bond that cleaves as a result of the addition of mesityl azide. The newly formed complex has In-N and Zn-N bonds. In the final part benzanthrone dyes containing intramolecular donor-acceptor interactions, (and hence, undergoing intramolecular charge transfer) were subject to the computational investigation of the mechanism of fluorescence taking place in them. Electronic excitations and the structure of first excited state in each case has been discussed thoroughly based on the time-dependent density functional theory. To check for the non-radiative loss of energy, we also performed calculations for the vertical excitations of the triplet states of all the molecules under study. To get a deeper insight into the intramolecular charge transfer, we performed NTO analysis that gives us information based on different colours in regions of charge accumulation and charge depletion.</p>

Noncovalent Interactions of 1,4-Dithiafulvene and Nitroaromatics: A Combined DFT and Ab Initio Molecular Dynamics (AIMD) Study

The noncovalent interactions between a redox-active molecule, phenyl-substituted dithiafulvene (Ph-DTF), and ten commonly encountered nitroaromatic compounds (NACs) were systematically investigated by means of density functional theory (DFT) calculations and ab initio molecular dynamics (AIMD) simulations. Our modeling studies examined their 1:1 complexes in terms of equilibrium geometries, frontier molecular orbitals (FMOs), nature of noncovalent forces, intermolecular charge transfer (ICT), interaction energies and related energy decomposition analysis. The computational results indicate that Ph-DTF can form thermodynamically stable supramolecular complexes with trinitro-substituted benzenes (e.g., 2,4,6-trinisuchtrotoluene and picric acid), but its interactions with mono- and dinitrobenzenes do not exhibit such stability. The selective binding properties are further corroborated by AIMD simulations. Overall, this computational work establishes a comprehensive understanding of the nature of noncovalent interactions of Ph-DTF with various NACs, and the results can be used as theoretical guidance for the rational design of selective receptors and/or chemosensors for certain NACs that are of great concern in current industrial applications and environmental control.

A Combined Experimental/Quantum-Chemical Study of Tetrel, Pnictogen, and Chalcogen Bonds of Linear Triatomic Molecules

Linear triatomic molecules (CO2, N2O, and OCS) are scrutinized for their propensity to form perpendicular tetrel (CO2 and OCS) or pnictogen (N2O) bonds with Lewis bases (dimethyl ether and trimethyl amine) as compared with their tendency to form end-on chalcogen bonds. Comparison of the IR spectra of the complexes with the corresponding monomers in cryogenic solutions in liquid argon enables to determine the stoichiometry and the nature of the complexes. In the present cases, perpendicular tetrel and pnictogen 1:1 complexes are identified mainly on the basis of the lifting of the degenerate ν 2 bending mode with the appearance of both a blue and a red shift. Van ′t Hoff plots of equilibrium constants as a function of temperature lead to complexation enthalpies that, when converted to complexation energies, form the first series of experimental complexation energies on sp1 tetrel bonds in the literature, directly comparable to quantum-chemically obtained values. Their order of magnitude corresponds with what can be expected on the basis of experimental work on halogen and chalcogen bonds and previous computational work on tetrel bonds. Both the order of magnitude and sequence are in fair agreement with both CCSD(T) and DFA calculations, certainly when taking into account the small differences in complexation energies of the different complexes (often not more than a few kJ mol−1) and the experimental error. It should, however, be noted that the OCS chalcogen complexes are not identified experimentally, most probably owing to entropic effects. For a given Lewis base, the stability sequence of the complexes is first successfully interpreted via a classical electrostatic quadrupole–dipole moment model, highlighting the importance of the magnitude and sign of the quadrupole moment of the Lewis acid. This approach is validated by a subsequent analysis of the molecular electrostatic potential, scrutinizing the σ and π holes, as well as the evolution in preference for chalcogen versus tetrel bonds when passing to “higher” chalcogens in agreement with the evolution of the quadrupole moment. The energy decomposition analysis gives further support to the importance/dominance of electrostatic effects, as it turns out to be the largest attractive term in all cases considered, followed by the orbital interaction and the dispersion term. The natural orbitals for chemical valence highlight the sequence of charge transfer in the orbital interaction term, which is dominated by an electron-donating effect of the N or O lone-pair(s) of the base to the central atom of the triatomics, with its value being lower than in the case of comparable halogen bonding situations. The effect is appreciably larger for TMA, in line with its much higher basicity than DME, explaining the comparable complexation energies for DME and TMA despite the much larger dipole moment for DME.

Interaction Energy Analysis of Monovalent Inorganic Anions in Bulk Water Versus Air/Water Interface

Soft anions exhibit surface activity at the air/water interface that can be probed using surface-sensitive vibrational spectroscopy, but the structural implications of this surface activity remain a matter of debate. Here, we examine the nature of anion–water interactions at the air/water interface using a combination of molecular dynamics simulations and quantum-mechanical energy decomposition analysis based on symmetry-adapted perturbation theory. Results are presented for a set of monovalent anions, including Cl−, Br−, I−, CN−, OCN−, SCN−, NO2−, NO3−, and ClOn− (n=1,2,3,4), several of which are archetypal examples of surface-active species. In all cases, we find that average anion–water interaction energies are systematically larger in bulk water although the difference (with respect to the same quantity computed in the interfacial environment) is well within the magnitude of the instantaneous fluctuations. Specifically for the surface-active species Br−(aq), I−(aq), ClO4−(aq), and SCN−(aq), and also for ClO−(aq), the charge-transfer (CT) energy is found to be larger at the interface than it is in bulk water, by an amount that is greater than the standard deviation of the fluctuations. The Cl−(aq) ion has a slightly larger CT energy at the interface, but NO3−(aq) does not; these two species are borderline cases where consensus is lacking regarding their surface activity. However, CT stabilization amounts to <20% of the total induction energy for each of the ions considered here, and CT-free polarization energies are systematically larger in bulk water in all cases. As such, the role of these effects in the surface activity of soft anions remains unclear. This analysis complements our recent work suggesting that the short-range solvation structure around these ions is scarcely different at the air/water interface from what it is in bulk water. Together, these observations suggest that changes in first-shell hydration structure around soft anions cannot explain observed surface activities.

Alkyne-Functionalized Cyclooctyne on Si(001): Reactivity Studies and Surface Bonding from an Energy Decomposition Analysis Perspective

The reactivity and bonding of an ethinyl-functionalized cyclooctyne on Si(001) is studied by means of density functional theory. This system is promising for the organic functionalization of semiconductors. Singly bonded adsorption structures are obtained by [2+2] cycloaddition reactions of the cyclooctyne or ethinyl group with the Si(001) surface. A thermodynamic preference for adsorption with the cyclooctyne group in the on-top position is found and traced back to minimal structural deformation of the adsorbate and surface with the help of energy decomposition analysis for extended systems (pEDA). Starting from singly bonded structures, a plethora of reaction paths describing conformer changes and consecutive reactions with the surface are discussed. Strongly exothermic and exergonic reactions to doubly bonded structures are presented, while small reaction barriers highlight the high reactivity of the studied organic molecule on the Si(001) surface. Dynamic aspects of the competitive bonding of the functional groups are addressed by ab initio molecular dynamics calculations. Several trajectories for the doubly bonded structures are obtained in agreement with calculations using the nudged elastic band approach. However, our findings disagree with the experimental observations of selective adsorption by the cyclooctyne moiety, which is critically discussed.