•Binding motifs of a previously proposed CCR5/CXCR4 dual tropic inhibitor are studied.•π-stacking and electrostatics drive binding between ligand and receptor residues.•Unfavorable desolvation of active site Glu and Asp residues offsets favorable motifs.•The replacement of the γ-carbon of the ligand piperidine ring deters such an offset.The human immunodeficiency virus (HIV) infects healthy human cells by binding to the glycoprotein cluster of differentiation 4 receptors on the surface of helper T-cells, along with either of two chemokine receptors, CC chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4). Recently, a pyrazolo-piperdine ligand was synthesized and the corresponding biological data showed good binding to both chemokine receptors, effectively blocking HIV-1 entry. Here, we exhaustively assess the atomistic binding interactions of this compound with both CCR5 and CXCR4, and we find that binding is driven by π-stacking interactions between aromatic rings on the ligand and receptor residues, as well as electrostatic interactions involving the protonated piperidine nitrogen. However, these favorable binding interactions were partially offset by unfavorable desolvation of active site glutamates and aspartates, prompting our proposal of a new, synthetically-accessible derivative designed to increase the electrostatic interactions without compromising the π-stacking features.Download high-res image (119KB)Download full-size image

•The dynamics and molecular mechanisms for binding between Dynemicin A and DNA are studied.•We find evidence for dynemicin A intercalating between two base pairs and directly abstracting a hydrogen atom from DNA.•We also find evidence of dynemicin A inserting into the minor groove and directly abstracting a hydrogen atom from DNA.•As well, we find a third mechanism whereby dynemicin A intercalates, then undergoes a proximate, intramolecular hydrogen atom abstraction (internal abstraction).Dynemicin A has the ability to undergo the Bergman cyclization, forming a para-benzyne moiety with the ability to induce DNA strand scission. This property of dynemicin A makes it a promising anti-tumor agent. Past research has shown conclusively that dynemicin A binds to and abstracts a hydrogen atom (H5′) from the DNA backbone, but the molecular mechanism of the binding event is not fully understood. We have used AMBER Molecular Dynamics simulations to investigate the dynamics associated with the reaction mechanisms. Previously, two binding mechanisms have been proposed, of which the second is more supported: (1) dynemicin A intercalates between two base pairs and directly abstracts a hydrogen atom from DNA and (2) dynemicin A inserts into the minor groove and directly abstracts a hydrogen atom from DNA. We propose a third mechanism, where dynemicin A intercalates, then undergoes a proximate, intramolecular hydrogen atom abstraction (internal abstraction). While not studied here, the resulting radical would then subsequently abstract a hydrogen atom from DNA.Download high-res image (131KB)Download full-size image

We investigated the symmetry breaking mechanism in cubic octa-tert-butyl silsesquioxane and octachloro silsesquioxane monocations (Si8O12(C(CH3)3)8+ and Si8O12Cl8+) using density functional theory (DFT) and group theory. Under Oh symmetry, these ions possess 2T2g and 2Eg electronic states and undergo different symmetry breaking mechanisms. The ground states of Si8O12(C(CH3)3)8+ and Si8O12Cl8+ belong to the C3v and D4h point groups and are characterized by Jahn–Teller stabilization energies of 3959 and 1328 cm–1, respectively, at the B3LYP/def2-SVP level of theory. The symmetry distortion mechanism in Si8O12Cl8+ is Jahn–Teller type, whereas in Si8O12(C(CH3)3)8+ the distortion is a combination of both Jahn–Teller and pseudo-Jahn–Teller effects. The distortion force acting in Si8O12(C(CH3)3)8+ is mainly localized on one Si–(tert-butyl) group, while in Si8O12Cl8+ it is distributed over the oxygen atoms. The main distortion forces acting on the Si8O12 core arise from the coupling between the electronic state and the vibrational modes, identified as 9t2g + 1eg + 3a2u for the Si8O12(C(CH3)3)8+ and 1eg + 2eg for Si8O12Cl8+.

Halogen bonding (R–X···Y) is a qualitative analogue of hydrogen bonding that may prove useful in the rational design of artificial proteins and nucleotides. We explore halogen-bonded DNA base pairs containing modified guanine, cytosine, adenine and thymine nucleosides. The structures and stabilities of the halogenated systems are compared to the normal hydrogen bonded base pairs. In most cases, energetically stable, coplanar structures are identified. In the most favorable cases, halogenated base pair stabilities are within 2 kcal mol–1 of the hydrogen bonded analogues. Among the halogens X = Cl, Br, and I, bromine is best suited for inclusion in these biological systems because it possesses the best combination of polarizability and steric suitability. We find that the most stable structures result from a single substitution of a hydrogen bond for a halogen bond in dA:dT and dG:dC base pairs, which allows 1 or 2 hydrogen bonds, respectively, to complement the halogen bond.

Mechanisms for the reaction of thiophene and 2-methylthiophene with molecular oxygen on both the triplet and singlet potential energy surfaces (PESs) have been investigated using ab initio methods. Geometries of various stationary points involved in the complex reaction routes are optimized at the MP2/6-311++G(d, p) level. The barriers and energies of reaction for all product channels were refined using single-point calculations at the G4MP2 level of theory. For thiophene, CCSD(T) single point energies were also determined for comparison with the G4MP2 energies. Thiophene and 2-methylthiophene were shown to react with O2 via two types of mechanisms, namely, direct hydrogen abstraction and addition/elimination. The barriers for reaction with triplet oxygen are all significantly large (i.e., >30 kcal mol–1), indicating that the direct oxidation of thiophene by ground state oxygen might be important only in high temperature processes. Reaction of thiophene with singlet oxygen via a 2 + 4 cycloaddition leading to endoperoxides is the most favorable channel. Moreover, it was found that alkylation of the thiophene ring (i.e., methyl-substituted thiophene) is capable of lowering the barrier height for the addition pathway. The implication of the current theoretical results may shed new light on the initiation mechanisms for combustion of asphaltenes.

Radical recombination reactions are important in the combustion of fuel oils. Shale oil contains alkylated heteroaromatic species, the simplest example of which is the 2-thienylmethyl radical. The ab initio potential energy surface for the reaction of the 2-thienylmethyl radical with the HO2 radical has been examined. Seventeen product channels corresponding to either addition/elimination or direct hydrogen abstraction have been characterized for the first time. Direct hydrogen abstract from HO2 proceeds via a weakly bound van der Waals complex, which leads to 2-methylthiophene, 2-methylene-2,3-dihydrothiophene, or 2-methylene-2,5-dihydrothiophene depending upon the 2-thienylmethyl radical reaction site. The addition pathway for the two radical reactants is barrierless with the formation of three adducts, as distinguished by HO2 reaction at three different sites on the 2-thienylmethyl radical. The addition is exothermic by 37–55 kcal mol–1 relative to the entrance channel, and these excess energies are available to promote further decomposition or rearrangement of the adducts, leading to nascent products such as H, OH, H2O, and CH2O. The reaction surfaces are characterized by relatively low barriers (most lower than 10 kcal mol–1). Upon the basis of a careful analysis of the overall barrier heights and reaction exothermicities, the formations of O2, OH, and H2O are likely to be important pathways in the radical recombination reactions of 2-thienylmethyl + HO2.

The pyrolysis mechanisms of thiophene in asphaltenes have been investigated theoretically using density functional and ab initio quantum chemical techniques. All of the possible reaction pathways were explored using B3LYP, MP2, and CBS-QB3 models. A comparison of the calculated heats of reaction with the available experimental values indicates that the CBS-QB3 level of theory is quantitatively reliable for calculating the energetic reaction paths of the title reactions. The pyrolysis process is initiated via four different types of hydrogen migrations. According to the reaction barrier heights, the dominant 1,2-H shift mechanism involves two competitive product channels, namely, C2H2 + CH2CS and CS + CH3CCH. The minor channels include the formation of CS + CH2CCH2, H2S + C4H2, HCS + CH2CCH, CS + CH2CHCH, H + C4H3S, and HS + C4H3. The methyl substitution effect was investigated with the pyrolysis of 2-methylthiophene and 3-methylthiophene. The energetics of such systems were very similar to that for unsubstituted thiophene, suggesting that thiophene alkylation may not play a significant role in the pyrolysis of asphaltene compounds.

(rac)-1,1′-Binaphthyl–based simple receptors 1 and 2 have been designed, synthesized and studied theoretically. The receptors utilize naphthyridine as the binding motifs for complexation of dicarboxylic acids in CHCl3. The emission of the BINOL moiety was monitored experimentally to ascertain the selectivity and sensitivity of the receptors. Receptor 1 distinguishes maleic acid from isomeric fumaric acid by exhibiting different fluorescence behavior and demonstrates stronger binding in the excited state. Modulation of the binding sites of 1 leads to a new receptor structure 2, which was found to be less efficient in distinguishing maleic from fumaric acid, fluorometrically. Both 1 and 2 also recognize other hydroxy di- and tricarboxylic acids. The binding interactions were monitored by 1H NMR, fluorescence and UV–vis spectroscopic methods. Structures of apo-hosts, guests and host–guest complexes were determined using force-field based conformational searching. Low energy ensembles were grouped into geometrically similar families, and low energy structures from each family were verified using B3LYP/6-31G*/PB-SCRF(CHCl3) calculations. The atomistic calculations provide insight into the differential dicarboxylic acid binding behavior of receptors 1 and 2.

A new triphenylamine-based receptor 1 has been designed and synthesized for the recognition of aliphatic dicarboxylates of various chain lengths. This receptor has been designed to utilize an amide–urea conjugate for binding dicarboxylates. The receptor 1 is found to bind the dicarboxylates with moderate binding strength under a semi rigid, propeller shaped, fluorescent triphenylamine spacer. The binding behavior was studied in CH3CN using 1H NMR, fluorescence and UV–vis spectroscopic methods. The conformational behavior of 1 and its complexation modes have been investigated using classical and quantum mechanical theoretical methods. The receptor is found to be selective for long chain suberate.A new triphenylamine-based receptor 1 has been designed and synthesized for the recognition of aliphatic dicarboxylates of various chain lengths. The receptor 1 is found to bind the dicarboxylates with moderate binding strength under a semi rigid, propeller-shaped, fluorescent triphenylamine spacer. The binding behavior was studied in CH3CN using 1H NMR, fluorescence, and UV–vis spectroscopic methods. The conformational behavior of 1 and its complexation modes have been investigated using classical and quantum mechanical theoretical methods. The receptor is found to be selective for long chain suberate.

9-Deaza-2′-deoxyguanosine (CdG) is a C-nucleoside and an analogue of the abundant promutagen 8-oxo-2′-deoxyguanosine (OdG). Like 2′-deoxyguanosine (dG), CdG should form a stable base pair with dC, but similar to OdG, CdG contains an N7-hydrogen that should allow it to also form a relatively stable base pair with dA. In order to further investigate the base pairing of CdG, it was incorporated into DNA and paired with either dC or dA. Melting studies revealed CdG:dC base pairs are less stable than dG:dC base pairs, while CdG:dA base pairs are less stable than OdG:dA base pairs. In order to gain a deeper understanding of these results, quantum studies on model structures of nucleoside monomers and base pairs were performed, the results of which indicate that (i) CdG:dC base pairs are likely destabilized relative to dG:dC as a result of structural constraints imposed by the C-nucleotide character of CdG, and (ii) CdG:dA base pairs may be less stable than OdG:dA base pairs, at least in part, because of a third long-range interaction that is possible in OdG:dA but not in CdG:dA.

An analysis of the conformational preferences of three trimeric maleimide substituted 1,5,9-triazacyclododecane derivatives, proposed as cross linking reagents for HIV-1 fusion inhibitors, is presented. Exhaustive sampling was performed using the mixed Low Mode Monte Carlo conformational searching technique on the corresponding OPLS2005/GBSA(water) potential energy surface. Geometric structure, molecular length, and hydrogen bonding patterns of the compounds are analyzed. Global minimum energy structures were verified as minima using B3LYP/6-31G∗ geometry optimization. All structures adopt a crown-like 12-membered ring conformation; however, the system with the shortest maleimide arms (1a) can also adopt alternative ring orientations. Overall, derivatives with longer maleimide arms were more flexible and resulted in ensembles with a larger number of low energy structures. Comparison with biological inhibition data indicates that there is very little relationship between molecular size and the ability of the scaffold to orient CD4M9 miniproteins for optimal inhibition; however hydrophobicity may play a role.

Homology models were built for various length sequences of the kinesin-1 light chain (KLC) domain of Drosophila melanogaster and subjected to 200 ns of all-atom molecular dynamics. We also cloned, expressed and characterized these regions spectroscopically. Results confirm that KLC contains tetratricopeptide repeat units; a regular array of repeating 34-residue helix–loop–helix monomers. Experimental and computational evidence is provided confirming the stability and overall helicity of individual TPR repeats as well as individual TPR units incorporated into a multi-TPR structure.

•DNA polymerase X-ray structure provides starting structure to investigate closing•MD simulations provide atomistic details of DNA polymerase closing•Propose sequence of events in prechemistry DNA polymerase active site assembly•Identify a conserved histidine as a potential proton acceptor to initiate catalysisDNA polymerases must quickly and accurately distinguish between similar nucleic acids to form Watson-Crick base pairs and avoid DNA replication errors. Deoxynucleoside triphosphate (dNTP) binding to the DNA polymerase active site induces a large conformational change that is difficult to characterize experimentally on an atomic level. Here, we report an X-ray crystal structure of DNA polymerase I bound to DNA in the open conformation with a dNTP present in the active site. We use this structure to computationally simulate the open to closed transition of DNA polymerase in the presence of a Watson-Crick base pair. Our microsecond simulations allowed us to characterize the key steps involved in active site assembly, and propose the sequence of events involved in the prechemistry steps of DNA polymerase catalysis. They also reveal new features of the polymerase mechanism, such as a conserved histidine as a potential proton acceptor from the primer 3′-hydroxyl.Download high-res image (265KB)Download full-size image