Simulation of interactions in the co-planar nucleic acid base pairs using atom-atom potential functions

Calculations of the energy of nucleic acid base interactions as a function of parameters determining mutual position of two bases in a plane have been performed. Atom-atom potential functions used include terms proportional to the first (electrostatic), sixth (or tenth for the atoms of hydrogen bond) and 12th power of interatomic distance. The calculations have shown the existence of 27 energy minima which correspond to the formation of co-planar pairs with two (or three for G : C pair) almost linear N--H...O and N--H...N hydrogen bonds. The positions of nitrogen bases bound by two hydrogen bonds in every crystal of nucleic acid components, in the complexes of polynucleotides and in tRNA are near to the positions in one of these minima. In addition for every pair there exist energy minima which correspond to the formation of one N--H...O or N--H...N and one C--H...O or C--H...N hydrogen bond. Energy behavior near minima have been investigated. The results of our calculations are in agreement with experimental data and with the calculations which employ quantum mechanical results.     

The occurrence of C--H...O hydrogen bonds in alpha-helices and helix termini in globular proteins

A comprehensive database analysis of C--H...O hydrogen bonds in 3124 alpha-helices and their corresponding helix termini has been carried out from a nonredundant data set of high-resolution globular protein structures resolved at better than 2.0 A in order to investigate their role in the helix, the important protein secondary structural element. The possible occurrence of 5 --> 1 C--H...O hydrogen bond between the ith residue CH group and (i - 4)th residue C==O with C...O < or = 3.8 A is studied, considering as potential donors the main-chain Calpha and the side-chain carbon atoms Cbeta, Cgamma, Cdelta and Cepsilon. Similar analysis has been carried out for 4 --> 1 C--H...O hydrogen bonds, since the C--H...O hydrogen bonds found in helices are predominantly of type 5 --> 1 or 4 --> 1. A total of 17,367 (9310 of type 5 --> 1 and 8057 of type 4 --> 1) C--H...O hydrogen bonds are found to satisfy the selected criteria. The average stereochemical parameters for the data set suggest that the observed C--H...O hydrogen bonds are attractive interactions. Our analysis reveals that the Cgamma and Cbeta hydrogen atom(s) are frequently involved in such hydrogen bonds. A marked preference is noticed for aliphatic beta-branched residue Ile to participate in 5 --> 1 C--H...O hydrogen bonds involving methylene Cgamma 1 atom as donor in alpha-helices. This may be an enthalpic compensation for the greater loss of side-chain conformational entropy for beta-branched amino acids due to the constraint on side-chain torsion angle, namely, chi1, when they occur in helices. The preference of amino acids for 4 --> 1 C--H...O hydrogen bonds is found to be more for Asp, Cys, and for aromatic residues Trp, Phe, and His. Interestingly, overall propensity for C--H...O hydrogen bonds shows that a majority of the helix favoring residues such as Met, Glu, Arg, Lys, Leu, and Gln, which also have large side-chains, prefer to be involved in such types of weak attractive interactions in helices. The amino acid side-chains that participate in C--H...O interactions are found to shield the acceptor carbonyl oxygen atom from the solvent. In addition, C--H...O hydrogen bonds are present along with helix stabilizing salt bridges. A novel helix terminating interaction motif, X-Gly with Gly at C(cap) position having 5 --> 1 Calpha--H...O, and a chain reversal structural motif having 1 --> 5 Calpha-H...O have been identified and discussed. Our analysis highlights that a multitude of local C--H...O hydrogen bonds formed by a variety of amino acid side-chains and Calpha hydrogen atoms occur in helices and more so at the helix termini. It may be surmised that the main-chain Calpha and the side-chain CH that participate in C--H...O hydrogen bonds collectively augment the cohesive energy and thereby contribute together with the classical N--H...O hydrogen bonds and other interactions to the overall stability of helix and therefore of proteins.     

Hydrogen bonds with pi-acceptors in proteins: frequencies and role in stabilizing local 3D structures

A comprehensive structural analysis of X--H...pi hydrogen bonding in proteins is performed based on 592 published high-resolution crystal structures (< or = 1.6 A). All potential donors and acceptors are considered, including acidic C--H groups. The sample contains 1311 putative X--H...pi hydrogen bonds with N--H, O--H or S--H donors, that is about one per 10.8 aromatic residues. By far the most efficient pi-acceptor is the side-chain of Trp, which accepts one X--H...pi hydrogen bond per 5.7 residues. The focus of the analysis is on recurrent structural patterns involving regular secondary structure elements. Numerous examples are found where peptide X--H...pi interactions are functional in stabilization of helix termini, strand ends, strand edges, beta-bulges and regular turns. Side-chain X--H...pi hydrogen bonds are formed in considerable numbers in alpha-helices and beta-sheets. Geometrical data on various types of X--H...pi hydrogen bonds are given.     

N-H...O, O-H...O, and C-H...O hydrogen bonds in protein-ligand complexes: strong and weak interactions in molecular recognition

The characteristics of N-H...O, O-H...O, and C-H...O hydrogen bonds are examined in a group of 28 high-resolution crystal structures of protein-ligand complexes from the Protein Data Bank and compared with interactions found in small-molecule crystal structures from the Cambridge Structural Database. It is found that both strong and weak hydrogen bonds are involved in ligand binding. Because of the prevalence of multifurcation, the restrictive geometrical criteria set up for hydrogen bonds in small-molecule crystal structures may need to be relaxed in macromolecular structures. For example, there are definite deviations from linearity for the hydrogen bonds in protein-ligand complexes. The formation of C-H...O hydrogen bonds is influenced by the activation of the C(alpha)-H atoms and by the flexibility of the side-chain atoms. In contrast to small-molecule structures, anticooperative geometries are common in the macromolecular structures studied here, and there is a gradual lengthening as the extent of furcation increases. C-H...O bonds formed by Gly, Phe, and Tyr residues are noteworthy. The numbers of hydrogen bond donors and acceptors agree with Lipinski's "rule of five" that predicts drug-like properties. Hydrogen bonds formed by water are also seen to be relevant in ligand binding. Ligand C-H...O(w) interactions are abundant when compared to N-H...O(w) and O-H...O(w). This suggests that ligands prefer to use their stronger hydrogen bond capabilities for use with the protein residues, leaving the weaker interactions to bind with water. In summary, the interplay between strong and weak interactions in ligand binding possibly leads to a satisfactory enthalpy-entropy balance. The implications of these results to crystallographic refinement and molecular dynamics software are discussed.     

Strong and weak hydrogen bonds in drug-DNA complexes: A statistical analysis

A statistical analysis of strong and weak hydrogen bonds in the minor groove of DNA was carried out for a set of 70 drug-DNA complexes. The terms ‘strong’ and ‘weak’ pertain to the inherent strengths and weakness of the donor and acceptor fragments rather than to any energy considerations. The dataset was extracted from the protein data bank (PDB). The analysis was performed with an in-house software, hydrogen bond analysis tool (HBAT). In addition to strong hydrogen bonds such as O—H⋯O and N—H⋯O, the ubiquitous presence of weak hydrogen bonds such as C—H⋯O is implicated in molecular recognition. On an average, there are 1.4 weak hydrogen bonds for every strong hydrogen bond. For both categories of interaction, the N(3) of purine and the O(2) of pyrimidine are favoured acceptors. Donor multifurcation is common with the donors generally present in the drug molecules, and shared by hydrogen bond acceptors in the minor groove. Bifurcation and trifurcation are most commonly observed. The metrics for strong hydrogen bonds are consistent with established trends. The geometries are variable for weak hydrogen bonds. A database of recognition geometries for 26 literature amidinium-based inhibitors of Human African Trypanosomes (HAT) was generated with a docking study using seven inhibitors which occur in published crystal structures included in the list of 70 complexes mentioned above, and 19 inhibitors for which the drug-DNA complex crystal structures are unknown. The virtual geometries so generated correlate well with published activities for these 26 inhibitors, justifying our assumption that strong and weak hydrogen bonds are optimized in the active site.     

C-H...O hydrogen bonds in the nuclear receptor RARgamma--a potential tool for drug selectivity

Hydrogen bonds between polarized atoms play a crucial role in protein interactions and are often used in drug design, which usually neglects the potential of C-H...O hydrogen bonds. The 1.4 A resolution crystal structure of the ligand binding domain of the retinoic acid receptor RARgamma complexed with the retinoid SR11254 reveals several types of C-H...O hydrogen bonds. A striking example is the hydroxyl group of the ligand that acts as an H bond donor and acceptor, leading to a synergy between classical and C-H...O hydrogen bonds. This interaction introduces both specificity and affinity within the hydrophobic ligand pocket. The similarity of intraprotein and protein-ligand C-H...O interactions suggests that such bonds should be considered in rational drug design approaches.     

Strong and weak hydrogen bonds in protein-ligand complexes of kinases: a comparative study

Strong and weak hydrogen bonds between protein and ligand are analyzed in a group of 233 X-ray crystal structures of the kinase family. These kinases are from both eukaryotic and prokaryotic organisms. The dataset comprises of 44 sub-families, out of which 35 are of human origin and the rest belong to other organisms. Interaction analysis was carried out in the active sites, defined here as a sphere of 10 A radius around the ligand. A majority of the interactions are observed between the main chain of the protein and the ligand atoms. As a donor, the ligand frequently interacts with amino acid residues like Leu, Glu and His. As an acceptor, the ligand interacts often with Gly, and Leu. Strong hydrogen bonds N-H...O, O-H...O, N-H...N and weak bonds C-H...O, C-H...N are common between the protein and ligand. The hydrogen bond donor capacity of Gly in N-H...O and C-H...O interactions is noteworthy. Similarly, the acceptor capacity of main chain Glu is ubiquitous in several kinase sub-families. Hydrogen bonds between protein and ligand form characteristic hydrogen bond patterns (supramolecular synthons). These synthon patterns are unique to each sub-family. The synthon locations are conserved across sub-families due to a higher percentage of conserved sequences in the active sites. The nature of active site water molecules was studied through a novel classification scheme, based on the extent of exposure of water molecules. Water which is least exposed usually participates in hydrogen bond formation with the ligand. These findings will help structural biologists, crystallographers and medicinal chemists to design better kinase inhibitors.     

Kinase inhibitors and the case for CH...O hydrogen bonds in protein-ligand binding

Although the hydrogen bond is known to be an important mediator of intermolecular interactions, there has yet to be an analysis of the role of CH...O hydrogen bonds in protein-ligand complexes. In this work, we present evidence for such nonstandard hydrogen bonds from a survey of aromatic ligands in 184 kinase crystal structures and 358 high-resolution structures from the Protein Data Bank. CH groups adjacent to the positively charged nitrogen of nicotinamide exhibit geometric preferences strongly suggestive of hydrogen bonding interactions, as do heterocyclic CH groups in kinase ligands, while other aromatic CH groups do not exhibit these characteristics. Ab initio calculations reveal a considerable range of CH...O hydrogen bonding potentials among different aromatic ring systems, with nicotinamide and heterocycles preferred in kinase inhibitors showing particularly favorable interactions. These results provide compelling evidence for the existence of CH...O hydrogen bonds in protein-ligand interactions, as well as information on the relative strength of various aromatic CH donors. Such knowledge will be of considerable value in protein modeling, ligand design, and structure-activity analysis.     

Interaction geometry involving planar groups in protein-protein interfaces

The geometry of interactions of planar residues is nonrandom in protein tertiary structures and gives rise to conventional, as well as nonconventional (X--H...pi, X--H...O, where X = C, N, or O) hydrogen bonds. Whether a similar geometry is maintained when the interaction is across the protein-protein interface is addressed here. The relative geometries of interactions involving planar residues, and the percentage of contacts giving rise to different types of hydrogen bonds are quite similar in protein structures and the biological interfaces formed by protein chains in homodimers and protein-protein heterocomplexes--thus pointing to the similarity of chemical interactions that occurs during protein folding and binding. However, the percentage is considerably smaller in the nonspecific and nonphysiological interfaces that are formed in crystal lattices of monomeric proteins. The C--H...O interaction linking the aromatic and the peptide groups is quite common in protein structures as well as the three types of interfaces. However, as the interfaces formed by crystal contacts are depleted in aromatic residues, the weaker hydrogen bond interactions would contribute less toward their stability.     

Analysis of structural water and CH···π interactions in HIV-1 protease and PTP1B complexes using a hydrogen bond prediction tool,HBPredicT

A hydrogen bond prediction tool HBPredicT is developed for detecting structural water molecules and CH···π interactions in PDB files of protein-ligand complexes. The program adds the missing hydrogen atoms to the protein, ligands, and oxygen atoms of water molecules and subsequently all the hydrogen bonds in the complex are located using specific geometrical criteria. Hydrogen bonds are classified into various types based on (i) donor and acceptor atoms, and interactions such as (ii) protein-protein, (iii) protein-ligand, (iv) protein-water, (v) ligand-water, (vi) water-water, and (vii) protein-water-ligand. Using the information in category (vii), the water molecules which form hydrogen bonds with the ligand and the protein simultaneously–the structural water–is identified and retrieved along with the associated ligand and protein residues. For CH···π interactions, the relevant portions of the corresponding structures are also extracted in the output. The application potential of this program is tested using 19 HIV-1 protease and 11 PTP1B inhibitor complexes. All the systems showed presence of structural water molecules and in several cases, the CH···π interaction between ligand and protein are detected. A rare occurrence of CH···π interactions emanating from both faces of a phenyl ring of the inhibitor is identified in HIV-1 protease 1D4L.     

The environment of amide groups in protein–ligand complexes: H-bonds and beyond

A comprehensive structural analysis of interactions involving amide NH and C=O groups in protein-ligand complexes has been performed based on 3,275 published crystal structures (resolution < or =2.5 A). Most of the amide C=O and NH groups at the protein-ligand interface are highly buried within the binding site and involved in H-bonds with corresponding counter-groups. Small percentages of C=O and NH groups are solvated or embedded in hydrophobic environments. In particular, C=O groups show a higher propensity to be solvated or embedded in a hydrophobic environment than NH groups do. A small percentage of carbonyl groups is involved in weak hydrogen bonds with CH. Cases of dipolar interactions, involving carbonyl oxygen and electrophilic carbon atoms, such as amide, amidinium, guanidium groups, are also identified. A higher percentage of NH are in contact with aromatic carbons, interacting either through hydrogen bonds (preferably with the NH group pointing towards a ring carbon atom) or through stacking between amide plane and ring plane. Comprehensive studies such as the present one are thought to be important for future improvements in the molecular design area, in particular for the development of new scoring functions. [Figure: see text].     

Helix packing motif common to the crystal structures of two undecapeptides containing dehydrophenylalanine residues: implications for the de novo design of helical bundle super secondary structural modules

De novo designed peptide based super secondary structures are expected to provide scaffolds for the incorporation of functional sites as in proteins. Self-association of peptide helices of similar screw sense, mediated by weak interactions, has been probed by the crystal structure determination of two closely related peptides: Ac-Gly1-Ala2-Delta Phe3-Leu4-Val5-DeltaPhe6-Leu7-Val8-DeltaPhe9-Ala10-Gly11-NH2 (I) and Ac-Gly1-Ala2-DeltaPhe3-Leu4-Ala5-DeltaPhe6-Leu7-Ala8-DeltaPhe9-Ala10-Gly11-NH2 (II). The crystal structures determined to atomic resolution and refined to R factors 8.12 and 4.01%, respectively, reveal right-handed 3(10)-helical conformations for both peptides. CD has also revealed the preferential formation of right-handed 3(10)-helical conformations for both molecules. Our aim was to critically analyze the packing of the helices in the solid state with a view to elicit clues for the design of super secondary structural motifs such as two, three, and four helical bundles based on helix-helix interactions. An important finding is that a packing motif could be identified common to both the structures, in which a given peptide helix is surrounded by six other helices reminiscent of transmembrane seven helical bundles. The outer helices are oriented either parallel or antiparallel to the central helix. The helices interact laterally through a combination of N--H...O, C--H...O, and C--H...pi hydrogen bonds. Layers of interacting leucine residues are seen in both peptide crystal structures. The packing of the peptide helices in the solid state appears to provide valuable leads for the design of super secondary structural modules such as two, three, or four helix bundles by connecting adjacent antiparallel helices through suitable linkers such as tetraglycine segments.     

Hydrogen bonds in crystal structures of amino acids, peptides and related molecules

The results of a survey of 439 hydrogen bonds in 95 recently determined crystal structures of amino acids, peptides and related molecules suggest that the following generalizations hold true for linear (angle X-H---Y greater than 150 degrees) hydrogen bonds. (1) The charge on the acceptor group does not influence the length of a hydrogen bond. (2) For a given acceptor group, the hydrogen bond lengths increase in the order imidazolium N--H less than ammonium N-H less than guanidinium N-H; this order holds true for oxygen anion acceptor groups. Cl-ions and the uncharged oxygen of water molecules. (3) The uncharged imidazole N-H group forms shorter hydrogen than the amide N-H GROUP. (4) The carboxyl O-H groups form shorter hydrogen bonds than other hydroxyl groups. (5) The hydrogen bonds involving a halogen ion are longer than hydrogen bonds with other acceptors when corrected for their longer van der Walls radii. The observed differences between the lengths of hydrogen bonds formed by different donor and acceptor groups in amino acids and peptides, imply differences in the energetics of their formation.     

Quantum-chemical analysis of C-H...O and C-H...N interactions in RNA base pairs--H-bond versus anti-H-bond pattern

Geometries and interaction energies of unusual UU and AA base pairs with one standard hydrogen bond (H-bond) and additional C-H...O or C-H...N contacts have been determined by quantum-chemical methods taking into account electron correlation. Whereas the C-H bond length in the UU C-H...O contact increases upon complex formation (H-bond pattern), the C-H bond of the AA C-H....N interaction is shortened (anti-H-bond pattern). The same properties are found for model complexes between U or A and formaldehyde that have intermolecular C-H...acceptor contacts but no standard H-bonds. Both the C-H...acceptor H-bond and anti-H-bond interactions are attractive. A possible influence of the donor CH group charge distribution on the interaction pattern is discussed.     

Peptide--water association in peptide crystals.

The structures of 37 peptide crystals, containing 78 water-peptide hydrogen bonds and 77 other hydrogen bonds involving water, were surveyed to identify the geometry of peptide backbone hydration. In the sample, hydration of peptide carbonyl occurred more frequently than hydration of peptide N--H. The most probable value of the C'=O ... O water angle was near 138 degrees, considerably greater than the 120 degrees to the axis of a lone electron pair on the carbonyl oxygen. Associated water oxygens tended to be in the plane of the peptide bond, bui--H and Ci+1=O atoms, was common in glycine-containing cyclic hexapeptides. The distribution of angles between two hydrogen bonds at a single water molecule, as defined by the three nonhydrogen atoms involved, was centered near the tetrahedral angle.     

Metal-activated histidine carbon donor hydrogen bonds contribute to metalloprotein folding and function

Carbon donor hydrogen bonds are typically weak interactions that contribute less than 2 kcal/mol, and provide only modest stabilization in proteins. One exception is the class of hydrogen bonds donated by heterocyclic side chain carbons. Histidine is capable of particularly strong interactions through the Cε¹ and Cδ² carbons when the imidazole is protonated or bound to metal. Given the frequent occurrence of metal-bound histidines in metalloproteins, we characterized the energies of these interactions through DFT calculations on model compounds. Imidazole-water hydrogen bonding could vary from −11.0 to −17.0 kcal/mol, depending on the metal identity and oxidation state. A geometric search of metalloprotein structures in the PDB identified a number of candidate His C-H···O hydrogen bonds which may be important for folding or function. DFT calculations on model complexes of superoxide reductase show a carbon donor hydrogen bond positioning a water molecule above the active site.     

Theoretical investigations on the hydrogen bonding of nitrile isomers with H2O,HF, NH3 and H2S

The hydrogen bonds formed by the interaction of nitriles with water, hydrogen fluoride, ammonia and hydrogen sulphide have been studied using B3LYP and second-order Møller–Plesset perturbation (MP2) methods and 6-311+ + G(d,p) basis set. The energies and structures of 80 hydrogen-bonded complexes between nitriles and small molecules were examined systematically using B3LYP and MP2 procedure. Categorisation of the hydrogen bonds involved in the various complexes led to an ordering of hydrogen bond donor and acceptor abilities for some functional groups. The interaction energies have been corrected for the basis set superposition error using Boy's counterpoise correction method. The Morokuma energy decomposition analysis reveals that the strong interactions are due to the attractive contributions from the electrostatic (ES), polarisation (PL) and charge transfer (CT) components. The topological parameters, electron density and Laplacian of electron density show excellent correlation with the hydrogen bond length. Natural bond orbital (NBO) analysis has also been performed to study the CT from proton acceptor to the antibonding orbital of the H–Y bond in the proton donor part of complexes. The frequency analysis of C–H…Y bond in the complexes indicates the blue-shifting nature largely in case of sp² hybridised carbon atom.     

Protein-ligand energetics assessed using deoxy and fluorodeoxy sugars in equilibrium binding and high resolution crystallographic studies.

Hydrogen bonding interactions are one of the most important single factors in protein-ligand interactions and molecular recognition. To probe the energetics of the interactions, we have analyzed the binding of 1-deoxy-, 2-deoxy- and 6-fluoro-6-deoxy- analogues of D-galactose (Gal) to a primary high-affinity periplasmic receptor for monosaccharide active transport. Kd values and atomic structures refined at 1.81 to 1.45 A resolution of the complexes have been determined and compared with those of Gal binding. With binding site residues and the bound modified sugars in nearly identical positions as found in the complex with Gal, the binding of 1-deoxy-Gal or 2-deoxy-Gal reflects the overall contribution of 1.8 kcal mol-1 per hydrogen bond (neutral-charge type) to the affinity of Gal. Neglected in these estimates is the contribution of van der Waals' forces that accompany the formation of hydrogen bonds with each sugar hydroxyl. Contrary to expectations, the 6-fluoro-6-deoxy analogue proved to be an inadequate probe of Gal OH6 as a hydrogen bond donor due to the binding of a new water molecule and structural changes arising from the electronegative fluoro group. This study sheds new light on the energetics of protein-ligand interactions and the use of engineered ligands in assessing these interactions.     

Bovine serum albumin observed by infrared spectrometry. II. Hydration mechanisms and interaction configurations of embedded H(2)O molecules

The hydration mechanism of bovine serum albumin (BSA) is studied, and we analyze (de)hydration spectra displayed previously. We first determine the three elementary (de)hydration spectra on which all these (de)hydration spectra can be decomposed. They correspond to three different hydration mechanisms for the protein, which we define after a quantitative analysis performed in a second step. The first mechanism, which involves ionization of carboxylic COOH groups, occurs at low hydration levels and rapidly reaches a plateau when the hygroscopy is increased. It is a mechanism that involves a single H(2)O molecule and consequently requires somewhat severe steric conditions. The second mechanism occurs at all hydration levels and, because it involves more H(2)O molecules, requires less severe steric conditions. It consists of the simultaneous hydration of one amide N--H group and one carbonyl-amide C=O group by four H(2)O molecules and one carboxyl COO(-) group by eight H(2)O molecules. The third mechanism is simpler and consists of the introduction of H(2)O molecules into the hydrogen-bond network of the hydrated protein. It becomes important at a high hydration level, when the presence of an appreciable number of H(2)O molecules makes this hydrogen-bond network well developed. This analysis also shows that 80 H(2)O molecules remain embedded in one dried protein made of 604 peptide units. They are held by hydrogen bonds established by N--H groups and at the same time they establish two hydrogen bonds on two carbonyl-amide C=O groups. The proportion of free N--H groups can be determined together with that of carbonyl-amide C=O groups accepting no hydrogen bonds and that of carbonyl-amide C=O groups accepting two hydrogen bonds. The proportion of N--H groups establishing one hydrogen bond directly on a carbonyl-amide C=O group is 65%, which is the proportion of peptide units found in alpha helices in BSA.