Benchmarking Water Models in Molecular Dynamics of Protein-Glycosaminoglycan Complexes.

Glycosaminoglycans (GAGs) made of repeating disaccharide units intricately engage with proteins, playing a crucial role in the spatial organization of the extracellular matrix (ECM) and the transduction of biological signals in cells to modulate a number of biochemical processes. Exploring protein-GAG interactions reveals several challenges for their analysis, namely, the highly charged and periodic nature of GAGs, their multipose binding, and the abundance of the interfacial water molecules in the protein-GAG complexes. Most of the studies on protein-GAG interactions are conducted using the TIP3P water model, and there are no data on the effect of various water models on the results obtained in molecular dynamics (MD) simulations of protein-GAG complexes. Hence, it is essential to perform a systematic analysis of different water models in MD simulations for these systems. In this work, we aim to evaluate the properties of the protein-GAG complexes in MD simulations using different explicit: TIP3P, SPC/E, TIP4P, TIP4PEw, OPC, and TIP5P and implicit: IGB = 1, 2, 5, 7, and 8 water models to find out which of them are best suited to study the dynamics of protein-GAG complexes. The FF14SB and GLYCAM06 force fields were used for the proteins and GAGs, respectively. The interactions of several GAG types, such as heparin, chondroitin sulfate, and hyaluronic acid with basic fibroblast growth factor, cathepsin K, and CD44 receptor, respectively, are investigated. The observed variations in different descriptors used to study the binding in these complexes emphasize the relevance of the choice of water models for the MD simulation of these complexes.

Molecular Electrostatic Potential Topology Analysis of Noncovalent Interactions.

ConspectusThe topology of molecular electrostatic potential (MESP), V(r), derived from a reliable quantum chemical method has been used as a powerful tool for the study of intermolecular noncovalent interactions. The MESP topology mapping is achieved by computing both ∇V(r) data and the elements of the Hessian matrix at ∇V(r) = 0, the critical point. MESP minimum (Vmin) as well as MESP at a reaction center, specific to an atom (Vn), have been employed as electronic parameters to interpret the variations in the reactivity (activation/deactivation) of chemical systems with respect to the influence of substituents, ligands, π-conjugation, aromaticity, trans influence, hybridization effects, steric effects, cooperativity, noncovalent interactions, etc. In this Account, several studies involving MESP topology analysis, which yielded interpretations of various noncovalent interactions and also provided new insights in the area of chemical bonding, are highlighted. The existence of lone pairs in molecules is distinctly reflected by the topology features of the MESP minima (Vmin). The Vmin is able to probe lone pairs in molecules, and it has been used as a reliable electronic parameter to assess their σ-donating power. Furthermore, MESP topology analysis can be used to forecast the structure and energetics of lone pair π-complexes. The MESP approach to rationalize lone pair interactions in molecular systems has led to the design of cyclic imines for CO2 capture. The MESP topology analysis of intermolecular complexes revealed a hitherto unknown phenomenon in chemical bonding theory─formation of a covalent bond due to the influence of a noncovalent bond. The MESP-guided approach to intermolecular interactions provided a successful design strategy for the development of CO2 capture systems. The MESP parameters Vmin and MESP at the nucleus, Vn, derived for the molecular systems have been used as powerful measures for the extent of electron donor-acceptor (eDA) interactions in noncovalent complexes. Noncovalent bond formation leads to more negative MESP at the acceptor nucleus (VnA) and less negative MESP at the donor nucleus (VnD). The strong linear relationship observed between ΔΔVn = ΔVnD - ΔVnA and bond energy suggested that MESP data provide a clear evidence of bond formation. Furthermore, MESP topology studies established a cooperativity rule for understanding the donor-acceptor interactive behavior of a dimer D...A with a third molecule. According to this, the electron reorganization in the dimer due to the eDA interaction enhances electron richness at "A", the acceptor, and enhances electron deficiency at "D", the donor. Resultantly, D in D...A is more accepting toward trimer formation, while A in D...A is more donating. MESP topology offers promising design strategies to tune the electron-donating strength in various noncovalent interactions in hydrogen-, dihydrogen-, halogen-, tetrel-, pnicogen-, chalcogen-, and aerogen-bonded complexes and thereby to predict the interactive behavior of molecules. To sum up, MESP topology analysis has become one of the most effective modern techniques for understanding, interpreting, and predicting the intermolecular interactive behavior of molecules.

Rh(I) and Organo-Rh(III) Complexes of meso-Triarylbiphenylcorrole.

Rhodium complexes of biphenylcorrole are reported, and the molecular structures of the complexes are unambiguously confirmed by single-crystal X-ray analysis. The adj-CCNN core of the dicarbacorrole efficiently stabilizes a rhodium metal ion in its two different oxidation states. It is pertinent to point out that the Rh(I) metal complex attains square-planar geometry while organo-Rh(III) forms an octahedral complex. Furthermore, density functional theory studies corroborate the experimental findings.

Fulleride-metal η5 sandwich and multi-decker sandwich complexes: A DFT prediction.

The (C60 CN)- formed by the reaction of CN- with fullerene shows high electron rich character, very similar to C60 ˙- , and it behaves as a large anion. Similar to Cp- , the bulky anion, (C60 CN)- , acts as a strong η5 ligand towards transition metal centers. Previous studies on η5 coordination of fullerene cage are reported for pseudo fullerenes whereas the present study deals with sandwich complexes of (C60 CN)- with Fe(II), Ru(II), Cr(II), Mo(II), and Ni(II) and multi-decker sandwich complexes of CN-fullerides with Fe(II). The structural parameters of these complexes and the corresponding Cp- complexes showed very close resemblance. Analysis of the metal-to-carbon bonding molecular orbitals showed that sandwich complex [Fe(η5 -(C60 CN)- )2 ] exhibit bonding features very similar to that of ferrocene. Also, a 6-fold decrease in the band gap energy is observed for [Fe(η5 -(C60 CN)- )2 ] compared to ferrocene. The energy of dissociation (ΔE) of the ligand (C60 CN)- from [Fe(η5 -(C60 CN)- )2 ] is slightly lower than the ΔE of a Cp* ligand from a ferrocene derivative wherein each cyclopentadienyl unit is substituted with four tertiary butyl groups. The (C60 CN)- ligand behaved as one of the bulkiest ligands in the chemistry of sandwich complexes. Further, the coordinating ability of the dianion, (C60 (CN)2 )2- is evaluated which showed strong coordination ability simultaneously with two metal centers leading to the formation of multi-decker sandwich and pearl-necklace type polymeric structures.

Studying specificity in protein-glycosaminoglycan recognition with umbrella sampling.

In the past few decades, glycosaminoglycan (GAG) research has been crucial for gaining insights into various physiological, pathological, and therapeutic aspects mediated by the direct interactions between the GAG molecules and diverse proteins. The structural and functional heterogeneities of GAGs as well as their ability to bind specific proteins are determined by the sugar composition of the GAG, the size of the GAG chains, and the degree and pattern of sulfation. A deep understanding of the interactions in protein-GAG complexes is essential to explain their biological functions. In this study, the umbrella sampling (US) approach is used to pull away a GAG ligand from the binding site and then pull it back in. We analyze the binding interactions between GAGs of three types (heparin, desulfated heparan sulfate, and chondroitin sulfate) with three different proteins (basic fibroblast growth factor, acidic fibroblast growth factor, and cathepsin K). The main focus of our study was to evaluate whether the US approach is able to reproduce experimentally obtained structures, and how useful it can be for getting a deeper understanding of GAG properties, especially protein recognition specificity and multipose binding. We found that the binding free energy landscape in the proximity of the GAG native binding pose is complex and implies the co-existence of several binding poses. The sliding of a GAG chain along a protein surface could be a potential mechanism of GAG particular sequence recognition by proteins.

Polyanionic cyano-fullerides for CO2 capture: a DFT prediction.

The reaction of C60 fullerene with 'n' molecules (n = 1 to 6) of 1,3-dimethyl-2,3-dihydro-2-cyano-imidazole (IMCN) results in the exothermic formation of imidazolium cation-polyanionic fulleride complexes, (IM+)n⋯((C60(CN)n)n-). The binding energy of IM+ with (C60(CN)n)n- in the imidazolium-fulleride ionic complexes increased from -69.6 kcal mol-1 for n = 1 to -202.9 kcal mol-1 for n = 6. The energetics of the complex formation and cation-anion interaction energy data suggest the formation of imidazolium-fulleride ionic liquid (IL) systems. Furthermore, the dimer formation of such ionic complexes showed more exergonic nature due to multiple cooperative electrostatic interactions between oppositely charged species and suggested improved energetics for higher order clusters. The molecular electrostatic potential (MESP) analysis has revealed that the extra 'n' electrons in the ionic complex as well as that in the bare (C60(CN)n)n- are delocalized mainly on the unsaturated carbon centers of the fullerene unit, while the CN groups remain as a neutral unit. The MESP minimum (Vmin) values of (C60(CN)n)n- on the carbon cage have shown that the addition of each CN- unit on the cage enhances the negative character of Vmin by ∼54.7 kcal mol-1. This enhancement in MESP is comparable to the enhancement observed when one electron is added to C60 to produce (-62.5 kcal mol-1) and suggests that adding 'n' CN- groups to the fullerene cage is equivalent to supplying 'n' electrons to the carbon cage. Also the high capacity of the fullerene cage to hold several electrons can be attributed to the spherical delocalization of them onto the electron deficient carbon cage. The interactive behavior of CO2 molecules with (IM+)n⋯(C60(CN)n)n- systems showed that the interaction becomes stronger from -2.3 kcal mol-1 for n = 1 to -18.6 kcal mol-1 for n = 6. From the trianionic fulleride onwards, the C⋯CO2 noncovalent (nc) interaction changes to C-CO2 covalent (c) interaction with the development of carboxylate character on the adsorbed CO2. These results prove that cyano-fullerides are promising candidates for CO2 capture.

Demarcating Noncovalent and Covalent Bond Territories: Imine-CO2 Complexes and Cooperative CO2 Capture.

Chemical bond territory is rich with covalently bonded molecules wherein a strong bond is formed by equal or unequal sharing of a quantum of electrons. The noncovalent version of the bonding scenarios expands the chemical bonding territory to a weak domain wherein the interplay of electrostatic and π-effects, dipole-dipole, dipole-induced dipole, and induced dipole-induced dipole interactions, and hydrophobic effects occur. Here we study both the covalent and noncovalent interactive behavior of cyclic and acyclic imine-based functional molecules (XN) with CO2. All parent XN systems preferred the formation of noncovalent (nc) complex XN···CO2, while more saturated such systems (XN') produced both nc and covalent (c) complexes XN'+-(CO2)-. In all such cases, crossover from an nc to c complex is clearly demarcated with the identification of a transition state (ts). The complexes XN'···CO2 and XN'+-(CO2)- are bond stretch isomers, and they define the weak and strong bonding territories, respectively, while the ts appears as the demarcation point of the two territories. Cluster formation of XN with CO2 reinforces the interaction between them, and all become covalent clusters of general formula (XN+-(CO2)-)n. The positive cooperativity associated with the NH···OC hydrogen bond formation between any two XN'+-(CO2)- units strengthened the N-C coordinate covalent bond and led to massive stabilization of the cluster. For instance, the stabilizing interaction between the XN unit with CO2 is increased from 2-7 kcal/mol range in a monomer complex to 14-31 kcal/mol range for the octamer cluster (XN'+-(CO2)-)8. The cooperativity effect compensates for the large reduction in the entropy of cluster formation. Several imine systems showed the exergonic formation of the cluster and are predicted as potential candidates for CO2 capture and conversion.

Imidazolium-fulleride ionic liquids - a DFT prediction.

Ionic liquids (ILs) exhibit tunable physicochemical properties due to the flexibility of being able to select their cation-anion combination from a large pool of ions. The size of the ions controls the properties of the ILs in the range from ionic to molecular, and thus large ions play an important role in regulating the melting temperature and viscosity. Here, we show that the exohedral addition of anionic X- moieties to C60 (X = H, F, OH, CN, NH2, and NO2) is a thermodynamically viable process for creating large X-fulleride anions (C60X)-. The addition of X- to C60 is modelled by locating the transition state for the reaction between C60 and 1,3-dimethyl-2X-imidazole (IMX) at the M06L/6-311++G(d,p)//M06L/6-31G(d,p) level. The reaction yields the ion-pair complex IM+⋯(C60X)- for X = H, F, OH, CN, NH2, and NO2 and the ordered pair of (activation free energy, reaction free energy) is found to be (14.5, 1.1), (6.1, 3.1), (16.7, 2.3), (14.7, -7.9), (27.9, 0.5) and (11.9, 12.4), respectively. The low barrier of the reactions suggests their feasibility. The reaction is slightly endergonic for X = H, F, OH, and NH2, while X = CN shows a significant exergonic character. The X-fulleride formation is not observed when X = Cl and Br. The ion-pair interactions (Eion-pair) observed for IM+⋯(C60X)- range from -64.0 to -73.0 kcal mol-1, which is substantially lower (∼10%) than the typically reported values for imidazolium-based ionic liquids such as [EMIm]+[trz]-, [EMIm]+[dc]-, [EMIm]+[dtrz]-, and [EMIm]+[NH2tz]-. The quantum theory of atoms in molecules (QTAIM) analysis showed that the C-X bonding in (C60X)- is covalent, while that in (IM+⋯X-)⋯C60 (for X = Cl and Br) is non-covalent. Furthermore, molecular electrostatic potential (MESP) analysis showed that the X-fulleride could behave as a large spherical anion due to the delocalization of the excess electron in the system over the entire carbon framework. The large anionic character of the X-fulleride is also revealed by the identification of several close lying local energy minima for the IM+⋯(C60X)- ion-pair. The low Eion-pair value, the significant contribution of dispersion to the Eion-pair and the spherical nature of the anion predict low-melting point and highly viscous IL formation from X-fullerides and the imidazolium cation.

Guanidine as a strong CO2 adsorbent: a DFT study on cooperative CO2 adsorption.

Among the various carbon capture and storage (CCS) technologies, the direct air capture (DAC) of CO2 by engineered chemical reactions on suitable adsorbents has attained more attention in recent times. Guanidine (G) is one of such promising adsorbent molecules for CO2 capture. Recently Lee et al. (Phys. Chem. Chem. Phys., 2015, 17, 10925-10933) reported an interaction energy (ΔE) of -5.5 kcal mol-1 for the GCO2 complex at the CCSD(T)/CBS level, which was one of the best non-covalent interactions observed for CO2 among several functional molecules. Here we show that the non-covalent GCO2 complex can transform to a strongly interacting G-CO2 covalent complex under the influence of multiple molecules of G and CO2. The study, conducted at M06-2X/6-311++G** level density functional theory, shows ΔE = -5.7 kcal mol-1 for GCO2 with an NC distance of 2.688 Å while almost a five-fold increase in ΔE (-27.5 kcal mol-1) is observed for the (G-CO2)8 cluster wherein the N-C distance is 1.444 Å. All the (G-CO2)n clusters (n = 2-10) show a strong N-CO2 covalent interaction with the N-C distance gradually decreasing from 1.479 Å for n = 2 to 1.444 Å for n = 8 ≅ 9, 10. The N-CO2 bonding gives (G+)-(CO2-) zwitterion character for G-CO2 and the charge-separated units preferred a cyclic arrangement in (G-CO2)n clusters due to the support of three strong intermolecular OHN hydrogen bonds from every CO2. The OHN interaction is also enhanced with an increase in the size of the cluster up to n = 8. The high ΔE is attributed to the large cooperativity associated with the N-CO2 and OHN interactions. The quantum theory of atoms in molecules (QTAIM) analysis confirms the nature and strength of such interactions, and finds that the total interaction energy is directly related to the sum of the electron density at the bond critical points of N-CO2 and OHN interactions. Further, molecular electrostatic potential analysis shows that the cyclic cluster is stabilized due to the delocalization of charges accumulated on the (G+)-(CO2-) zwitterion via multiple OHN interactions. The cyclic (G-CO2)n cluster formation is a highly exergonic process, which reveals the high CO2 adsorption capability of guanidine.

Endo- and exohedral chloro-fulleride as η5 ligands: a DFT study on the first-row transition metal complexes.

C60 fullerene coordinates to transition metals in η2-fashion through its C-C bond at the 6-6 ring fusion site, whereas other coordination modes η3, η4, η5 and η6 are rarely observed. The coordination power of C60 to transition metals is weak owing to the inherent π-electron deficiency on each C-C bond as 60 electrons get delocalized over 90 bonds. The encapsulation of Cl- by C60 describes a highly exothermic reaction and the resulting Cl-@C60 behaves as a large anion. Similarly, the exohedral chloro-fulleride Cl-C60 acts as an electron-rich ligand towards metal coordination. A comparison of the coordinating ability of Cl-@C60 and Cl-C60 with that of the Cp- ligand is done for early to late transition metals of the first row using the M06L/6-31G** level of density functional theory. The binding energy (Eb) for the formation of endohedral (Cl-@C60)(MLn)+ and exohedral (Cl-C60)(MLn)+ complexes by the chloro-fulleride ligands ranges from -116 to -170 kcal mol-1 and from -111 to -173 kcal mol-1, respectively. Variation in Eb is also assessed for the effect of solvation by o-dichlorobenzene using a self-consistent reaction field method which showed 69-88% reduction in the binding affinity owing to more stabilization of the cationic and anionic fragments in the solvent compared to the neutral product complex. For each (Cl-@C60)(MLn)+ and (Cl-C60)(MLn)+ complex, the energetics for the transformation to C60 and MLnCl is evaluated which showed exothermic character for all endohedral and exohedral Co(i) and Ni(ii) complexes. The rest of the exohedral complexes, viz. Sc(i), Ti(ii), Ti(iv), V(i), Cr(ii), Mn(i), Fe(ii) and Cu(i) systems showed endothermic values in the range 2-35 kcal mol-1. The anionic modification makes the C60 unit a strong η5 ligand similar to Cp- for cationic transition metal fragments. The bulky anionic nature and strong coordination ability of chloro-fulleride ligands suggest new design strategies for organometallic catalysts.

Formation of large clusters of CO2 around anions: DFT study reveals cooperative CO2 adsorption.

The structure and energetics of the interaction of CO2 molecules with anions F-, Cl-, Br-, CN-, NC-, OH-, ClO-, NH2-, and NO2-, have been studied at the M06L/6-311++G** level of density functional theory. The maximum number of CO2 molecules (nmax) adsorbed by the anions to saturate the first shell of coordination varies from 8 to 12 in different complexes. The anionCO2 distance (dint) in F-(CO2), NC-(CO2), ClO-(CO2), HO-(CO2) and H2N-(CO2) is 1.533, 1.527, 1.468, 1.456, and 1.470 Å, respectively, which indicates covalent bond formation between carbon and the anion, which is confirmed from the interaction energy (Eint) values of these complexes 29.0, 14.7, 23.2, 41.7, and 48.1 kcal mol-1, respectively. The Cl-, Br-, CN- and NO2- interact always non-covalently with the carbon center of CO2 with dint in the range of 2.5-2.9 Å. With the adsorption of each CO2, an average increment of 5.9-6.7 kcal mol-1 is observed in the Eint value of the complexes. The Eint per CO2 (Eint/CO2) is nearly a constant for all the non-covalent complexes, even up to nmax number of CO2 adsorbed. Though the primary anionCO2 interaction gets weaker with the increasing size of the CO2 cluster, a steady increase in the secondary OC interaction between adsorbed CO2 molecules helps the systems to maintain a constant value for Eint/CO2. The electron density data of non-covalent bond critical points in quantum theory of atoms in molecules (QTAIM) analysis are used to partition the total interaction energy data into primary anionC and secondary OC interactions. Furthermore, the multicenter charge delocalization in the anionic complexes is explained using the molecular electrostatic potential (MESP) analysis. This study proves that the anions possess a remarkable ability to interact with a large number of CO2 molecules due to cooperativity resulting from the secondary OC interactions which compensate for the weakening of the primary anionC interactions. This property of the anion-CO2 interactions can be exploited for developing anionic or anion-incorporated materials for CO2 storage.