Halogen-Bonded Guanine Base Pairs, Quartets and Ribbons.
ABSTRACT: Halogen bonding is studied in different structures consisting of halogenated guanine DNA bases, including the Hoogsteen guanine-guanine base pair, two different types of guanine ribbons (R-I and R-II) consisting of two or three monomers, and guanine quartets. In the halogenated base pairs (except the Cl-base pair, which has a very non-planar structure with no halogen bonds) and R-I ribbons (except the At trimer), the potential N-X•••O interaction is sacrificed to optimise the N-X•••N halogen bond. In the At trimer, the astatines originally bonded to N1 in the halogen bond donating guanines have moved to the adjacent O6 atom, enabling O-At•••N, N-At•••O, and N-At•••At halogen bonds. The brominated and chlorinated R-II trimers contain two N-X•••N and two N-X•••O halogen bonds, whereas in the iodinated and astatinated trimers, one of the N-X•••N halogen bonds is lost. The corresponding R-II dimers keep the same halogen bond patterns. The G-quartets display a rich diversity of symmetries and halogen bond patterns, including N-X•••N, N-X•••O, N-X•••X, O-X•••X, and O-X•••O halogen bonds (the latter two facilitated by the transfer of halogens from N1 to O6). In general, halogenation decreases the stability of the structures. However, the stability increases with the increasing atomic number of the halogen, and the At-doped R-I trimer and the three most stable At-doped quartets are more stable than their hydrogenated counterparts. Significant deviations from linearity are found for some of the halogen bonds (with halogen bond angles around 150°).
Project description:In the title compound, C(17)H(18)N(4)O(5)·2C(3)H(7)NO, two solvent mol-ecules are linked to the main mol-ecule via N-H?O and O-H?O hydrogen bonds, forming a hydrogen-bonded trimer. Intra-molecular O-H?N hydrogen bonds influence the mol-ecular conformation of the main mol-ecule, and the two benzene rings form a dihedral angle of 10.55?(18)°. In the crystal, inter-molecular O-H?O hydrogen bonds link hydrogen-bonded trimers into ribbons extending along the b axis.
Project description:Halogen bonding in ligand-protein complexes is currently widely exploited, e.g. in drug design or supramolecular chemistry. But little attention has been directed to other effects that may result from replacement of a hydrogen by a strongly electronegative halogen. Analysis of almost 30000 hydrogen bonds between protein and ligand demonstrates that the length of a hydrogen bond depends on the type of donor-acceptor pair. Interestingly, lengths of hydrogen bonds between a protein and a halogenated ligand are visibly shorter than those estimated for the same family of proteins in complexes with non-halogenated ligands. Taking into account the effect of halogenation on hydrogen bonding is thus important when evaluating structural and/or energetic parameters of ligand-protein complexes. All these observations are consistent with the concept that halogenation increases the acidity of the proximal amino/imino/hydroxyl groups and thus makes them better, i.e. stronger, H-bond donors.
Project description:The quality of the force field is crucial to ensure the accuracy of simulations used in molecular modeling, including computer-aided drug design (CADD). To perform more accurate modeling and simulations of halogenated molecules, in this study the polarizable force field based on the classical Drude oscillator model was extended to both aliphatic and aromatic systems using halogenated ethane and benzene model compounds for the halogens F, Cl, Br, and I. The force field parameters were optimized targeting quantum mechanical dipole moments, water interactions, and molecular polarizabilities as well as experimental observables, including enthalpies of vaporization, molecular volumes, hydration free energies, and dielectric constants. The developed halogenated polarizable force field is capable of reproducing QM relative energies and geometries of both halogen bonds and halogen-hydrogen bond donor interactions at an unprecedented level due to the inclusion of a virtual particle and anisotropic atomic polarizability on the halogen and, notably, the inclusion of Lennard-Jones parameters on the halogen Drude particle. The model was validated on the basis of its ability to accurately reproduce pure solvent properties for halogenated naphthalenes and alkanes, including species analogous to those used as refrigerants. Accordingly, it is anticipated that the model will be applicable for the study of halogenated derivatives in CADD as well as in other chemical and biophysical studies.
Project description:We investigated whether there is any association between a native-like conformation and the presence of only the canonical (i.e., native) disulfide bonds in the gp120 subunits of a soluble recombinant human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein. We used a mass spectrometry (MS)-based method to map the disulfide bonds present in nonnative uncleaved gp140 proteins and native-like SOSIP.664 trimers based on the BG505 env gene. Our results show that uncleaved gp140 proteins were not homogeneous, in that substantial subpopulations (20 to 80%) contained aberrant disulfide bonds. In contrast, the gp120 subunits of the native-like SOSIP.664 trimer almost exclusively retained the canonical disulfide bond pattern. We also observed that the purification method could influence the proportion of an Env protein population that contained aberrant disulfide bonds. We infer that gp140 proteins may always contain a variable but substantial proportion of aberrant disulfide bonds but that the impact of this problem can be minimized via design and/or purification strategies that yield native-like trimers. The same factors may also be relevant to the production and purification of monomeric gp120 proteins that are free of aberrant disulfide bonds.It is widely thought that a successful HIV-1 vaccine will include a recombinant form of the Env protein, a trimer located on the virion surface. To increase yield and simplify purification, Env proteins are often made in truncated, soluble forms. A consequence, however, can be the loss of the native conformation concomitant with the virion-associated trimer. Moreover, some soluble recombinant Env proteins contain aberrant disulfide bonds that are not expected to be present in the native trimer. To assess whether these observations are linked, to determine the extent of disulfide bond scrambling, and to understand why scrambling occurs, we determined the disulfide bond profiles of two soluble Env proteins with different designs that are being assessed as vaccine candidates. We found that uncleaved gp140 forms heterogeneous mixtures in which aberrant disulfide bonds abound. In contrast, BG505 SOSIP.664 trimers are more homogeneous, native-like entities that contain predominantly the native disulfide bond profile.
Project description:Halogen bonding has emerged as a promising tool in two-dimensional (2D) crystal engineering. Since halogen bonds are similar to hydrogen bonds in a number of aspects, the existing knowledge of hydrogen bonded systems can be applied to halogenated systems. Here we evaluate the applicability of a retrosynthetic approach based on topological similarity between hydrogen and halogen bonds to obtain predictable halogen bonded networks. The self-assembly of 1,3-dibromo-5-alkoxybenzene derivatives was studied in analogy with well-explored alkoxy isophthalic acids using a combination of experimental and theoretical tools. Scanning tunneling microscopy (STM) characterization of the networks formed at the liquid-graphite interface revealed that while the retrosynthetic approach works at the level of small clusters of molecules within the 2D network, the overall structure of the network deviates from the anticipated structure. The monolayers consist of fractured rows of halogen-bonded modules instead of the expected continuous lamellar structure. Each module consists of a discrete number of halogen-bonded molecules. The interactions responsible for the stabilization of halogen bonded dimers are delineated through detailed density functional theory (DFT) calculations coupled with natural bonding orbitals (NBO) and perturbation analysis. A modified force field that includes an extra charged site to imitate the σ hole on the halogen atom was developed and applied to extract total potential energies of the anticipated and observed networks. Plausible reasons for the deviation from the anticipated structure are discussed. Finally, a modified molecular design that allows successful application of the hydrogen bond-halogen bond analogy was tested experimentally.
Project description:The concept of the halogen bond (or X-bond) has become recognized as contributing significantly to the specificity in recognition of a large class of halogenated compounds. The interaction is most easily understood as primarily an electrostatically driven molecular interaction, where an electropositive crown, or ?-hole, serves as a Lewis acid to attract a variety of electron-rich Lewis bases, in analogous fashion to a classic hydrogen bonding (H-bond) interaction. We present here a broad overview of X-bonds from the perspective of a biologist who may not be familiar with this recently rediscovered class of interactions and, consequently, may be interested in how they can be applied as a highly directional and specific component of the molecular toolbox. This overview includes a discussion for where X-bonds are found in biomolecular structures, and how their structure-energy relationships are studied experimentally and modeled computationally. In total, our understanding of these basic concepts will allow X-bonds to be incorporated into strategies for the rational design of new halogenated inhibitors against biomolecular targets or toward molecular engineering of new biological-based materials.
Project description:A successful HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (bNAbs) that target the envelope glycoprotein (Env) spike on the virus. Native-like recombinant Env trimers of the SOSIP design now serve as a platform for achieving this challenging goal. However, SOSIP trimers usually do not bind efficiently to the inferred germline precursors of bNAbs (gl-bNAbs). We hypothesized that the inherent flexibilities of the V1 and V2 variable loops in the Env trimer contribute to the poor recognition of gl-bNAb epitopes at the trimer apex that extensively involve V2 residues. To reduce local V2 flexibility and improve the binding of V2-dependent bNAbs and gl-bNAbs, we designed BG505 SOSIP.664 trimer variants containing newly created disulfide bonds intended to stabilize the V2 loop in an optimally antigenic configuration. The first variant, I184C/E190C, contained a new disulfide bond within the V2 loop, whereas the second variant, E153C/R178C, had a new disulfide bond that cross-linked V2 and V1. The resulting engineered native-like trimer variants were both more reactive with and were neutralized by V2 bNAbs and gl-bNAbs, a finding that may be valuable in the design of germline targeting and boosting trimer immunogens to create an antigenic conformation optimal for HIV vaccine development.
Project description:Halogen bonds are highly important in medicinal chemistry as halogenation of drugs, generally, improves both selectivity and efficacy toward protein active sites. However, accurate modeling of halogen bond interactions remains a challenge, since a thorough theoretical investigation of the bonding mechanism, focusing on the realistic complexity of drug-receptor systems, is lacking. Our systematic quantum-chemical study on ligand/peptide-like systems reveals that halogen bonding is driven by the same bonding interactions as hydrogen bonding. Besides the electrostatic and the dispersion interactions, our bonding analyses, based on quantitative Kohn-Sham molecular orbital theory together with energy decomposition analysis, reveal that donor-acceptor interactions and steric repulsion between the occupied orbitals of the halogenated ligand and the protein need to be considered more carefully within the drug design process.
Project description:Chronic inflammation is closely associated with cancer development. One possible mechanism for inflammation-induced carcinogenesis is DNA damage caused by reactive halogen species, such as hypochlorous acid, which is released by myeloperoxidase to kill pathogens. Hypochlorous acid can attack genomic DNA to produce 8-chloro-2'-deoxyguanosine (ClG) as a major lesion. It has been postulated that ClG promotes mutagenic replication using its syn conformer; yet, the structural basis for ClG-induced mutagenesis is unknown. We obtained crystal structures and kinetics data for nucleotide incorporation past a templating ClG using human DNA polymerase ? (pol?) as a model enzyme for high-fidelity DNA polymerases. The structures showed that ClG formed base pairs with incoming dCTP and dGTP using its anti and syn conformers, respectively. Kinetic studies showed that pol? incorporated dGTP only 15-fold less efficiently than dCTP, suggesting that replication across ClG is promutagenic. Two hydrogen bonds between syn-ClG and anti-dGTP and a water-mediated hydrogen bond appeared to facilitate mutagenic replication opposite the major halogenated guanine lesion. These results suggest that ClG in DNA promotes G to C transversion mutations by forming Hoogsteen base pairing between syn-ClG and anti-G during DNA synthesis.
Project description:Halogen bonds have recently gained attention in life sciences and drug discovery. However, it can be difficult to harness their full potential, when newly introducing them into an established hit or lead structure by molecular design. A possible solution to overcome this problem is the use of halogen-enriched fragment libraries (HEFLibs), which consist of chemical probes that provide the opportunity to identify halogen bonds as one of the main features of the binding mode. Initially, we have suggested the HEFLibs concept when constructing a focused library for finding p53 mutant stabilizers. Herein, we broaden and extent this concept aiming for a general HEFLib comprising a huge diversity of binding motifs and, thus, increasing the applicability to various targets. Using the construction principle of feature trees, we represent each halogenated fragment by treating all simple to complex substituents as modifiers of the central (hetero)arylhalide. This approach allows us to focus on the proximal binding interface around the halogen bond and, thus, its integration into a network of interactions based on the fragment's binding motif. As a first illustrative example, we generated a library of 198 fragments that unifies a two-fold strategy: Besides achieving a diversity-optimized basis of the library, we have extended this "core" by structurally similar "satellite compounds" that exhibit quite different halogen bonding interfaces. Tuning effects, i.e., increasing the magnitude of the ?-hole, can have an essential influence on the strength of the halogen bond. We were able to implement this key feature into the diversity selection, based on the rapid and efficient prediction of the highest positive electrostatic potential on the electron isodensity surface, representing the ?-hole, by VmaxPred.