Interchain Crosslinking Research Articles

Thermal crosslinking of a novel membrane derived from phenolphthalein-based cardo poly(arylene ether ketone) to enhance CO2/CH4 separation performance and plasticization resistance

A novel gas separation membrane was fabricated from a commercially available polymer of phenolphthalein-based cardo poly (arylene ether ketone) (PEK-C). Thermal treatment was employed to improve the gas permeability and anti-plasticization property of PEK-C polymeric membrane via inducing interchain crosslinking. The changes of chemical structure, thermal crosslinking reaction, interchain distance, gas separation performance and anti-plasticization properties of PEK-C membranes were investigated by the FT-IR, XPS, TG-MS, XRD and gas permeation tests. Results show that the gas separation performance and anti-plasticization properties of PEK-C membranes are significantly enhanced after the thermal crosslinking, which is induced by the decomposition of the lactone rings in cardo moieties and crosslinking with the formation of biphenyl linkages. The dramatic enhancement in gas permeability for the crosslinked membrane is attributed to the enlargement of the interchain distance and free volume cavity, and the great improvement on the anti-plasticization property is due to the formation of a rigid crosslinked network structure. Compared to PEK-C polymeric membrane, the CO2 permeability of the crosslinked membrane increased by more than 110 times with an adequate CO2/CH4 selectivity, especially for the separation of CO2/CH4 mixed gas (50:50 mol%). The CO2 plasticization pressure substantially increased from 2 atm to the highest tested pressure of 30 atm. The gas separation performance of the crosslinked membrane surpassed the 2008 upper bound for CO2/CH4, exhibiting that the thermal crosslinking membrane derived from PEK-C membrane material is an attractive candidate for the natural gas purification.

Synthesis and properties of waterborne polyurethane/hydroxyapatite chemical hybrids

A series of waterborne polyurethane (WPU)/hydroxyapatite (HAP) chemical hybrids were synthesized from polypropylene glycol (PPG), 4, 4′-methylenebis cyclohexyl isocyanate (H12MDI), dimethylbutanic acid (DMBA), 2-hydroxyethyl acrylate (HEA), and vinyltrimethoxysilane (VTMS) modified HAP. Interchain siloxane bridges were introduced among the VTMS modified HAPs via sol-gel reaction while vinyl groups of VTMS segments were UV cured with HEA termini of WPU to form interchain croslinkings. In this way HAP provided WPU with internal and interchain crosslinks as well as reinforcing filler to augment thermal, mechanical, and surface properties. Glass transition temperature (Tg), contact angle, hardness, water swell resistance, and tensile modulus and strength increased with HAP inclusion showing maximum at 2% beyond which the effects were less pronounced owing to the agglomeration of HAP nanoparticles in water phase.

Influence of divalent counterions on the solution rheology and supramolecular aggregation of carboxymethyl cellulose

Divalent counterions promote attractive forces between polyelectrolyte chains via electrostatic bridging, which play an important role in the conformation of ionic biopolymers. Further, counterion valence is known to affect the flexibility and aggregation properties of polyelectrolytes in solution. The present study seeks to resolve the effect of counterion valence and type on the structure and flow properties of a model semiflexible polyelectrolyte. We report rheology and light scattering data for the Na $$^+$$ , Mg $$^{2+}$$ , Ca $$^{2+}$$ , Mn $$^{2+}$$ , Co $$^{2+}$$ , Ba $$^{2+}$$ salts of carboxymethyl cellulose in aqueous solutions. The Na $$^+$$ and Mg $$^{2+}$$ counterions do not interact specifically with the carboxylate groups, and their CMC salts form clear solutions in the concentration (c) range studied (0.001 M 0.2 M. Compared NaCMC, divalent salts display a lower viscosities at low concentrations (in the non-entangled regime), suggesting less expanded chains, in agreement with earlier experimental results on flexible polyelectrolytes. Above the entanglement crossover ( $$c \simeq$$ 0.07 M), solutions with divalent counterions display viscosities up to an order of magnitude larger than NaCMC, possibly because interchain crosslinks form by electrostatic bridging. Dynamic light scattering measurements on semidilute non-entangled solutions reveal a bimodal decay function, where the relative amplitudes of the two modes vary with counterion valence, size as well as with the filter size employed and the time after filtration. These variables (except for counterion valency) do not strongly affect the solution viscosity, indicating that polyelectrolyte clusters only contain a small fraction of the total number of chains in solution.

The Chain Distribution Tensor: Linking Nonlinear Rheology and Chain Anisotropy in Transient Polymers.

Transient polymer networks are ubiquitous in natural and engineered materials and contain cross-links that can reversibly break and re-form. The dynamic nature of these bonds allows for interesting mechanical behavior, some of which include nonlinear rheological phenomena such as shear thickening and shear thinning. Specifically, physically cross-linked networks with reversible bonds are typically observed to have viscosities that depend nonlinearly on shear rate and can be characterized by three flow regimes. In slow shear, they behave like Newtonian fluids with a constant viscosity. With further increase in shear rate, the viscosity increases nonlinearly to subsequently reach a maximum value at the critical shear rate. At this point, network fracture occurs followed by a reduction in viscosity (shear-thinning) with a further increase in shear rate. The underlying mechanism of shear thickening in this process is still unclear with debates between a conversion of intra-chain to inter-chain cross-linking and nonlinear chain stretch under high tension. In this paper, we provide a new framework to describe the nonlinear rheology of transient polymer networks with the so-called chain distribution tensor using recent advances from the transient network theory. This tensor contains quantitatively and statistical information of the chain alignment and possible anisotropy that affect network behavior and mechanics. We investigate shear thickening as a primary result of non-Gaussian chain behavior and derive a relationship for the nonlinear viscosity in terms of the non-dimensional Weissenberg number. We further address the criterion for network fracture at the critical shear rate by introducing a critical chain force when bond dissociation is suddenly accelerated. Finally, we discuss the role of cross-linker density on viscosity using a “sticky” reptation mechanism in the context of previous studies on metallo-supramolecular networks with reversible cross-linkers.

Effective Reduction of Volumetric Thermal Expansion of Aromatic Polyimide Films by Incorporating Interchain Crosslinking.

To develop a facile method for reducing the coefficient of volumetric thermal expansion (CVE) of polymer films, the thermal expansion behaviors of thermally cross-linkable polyimide (PI) films with isomeric diamine structures were investigated via thermal mechanical analyses and optical interferometry measurements. The degree of crosslinking of the PI films containing the diphenylethynylene (Ph–C≡C–Ph) structure in the main chain was characterized by far-infrared (far-IR) spectra and density functional theory (DFT) calculations, and variations in the CVE induced by thermal crosslinking were quantitatively estimated. The crosslinking reactions effectively reduced the CVEs of the PI films by suppressing intermolecular free volume expansion and local molecular motions promoted at elevated temperatures. The lowest CVE value observed for a crosslinked PI cured at 400 °C (+98 ppm/K at 80–280 °C) was one of the smallest values reported to date in polymers. Incorporating interchain crosslinking into the main chain is an effective method for reducing the CVE of aromatic polymers.

Computational investigation of microgels: synthesis and effect of the microstructure on the deswelling behavior.

We present computer simulations of a realistic model of microgels. Unlike the regular network frameworks usually assumed in the simulation literature, we model and simulate a realistic and efficient synthesis route, mimicking cross-linking of functionalized chains inside a cavity. This model is inspired, e.g., by microfluidic fabrication of microgels from macromolecular precursors and is different from standard polymerization routes. The assembly of the chains is mediated by a low fraction of interchain crosslinks. The microgels are polydisperse in size and shape but globally spherical objects. In order to deeply understand the microgel structure and eventually improve the synthesis protocol we characterize their conformational properties and deswelling kinetics, and compare them with the results found for microgels obtained via underlying regular (diamond-like) structures. For the same molecular weight, monomer concentration and effective degree of cross-linking, the specific microstructure of the microgel has no significant effect on the locus of the volume phase transition (VPT). However, it strongly affects the deswelling kinetics, as revealed by a consistent analysis of the domain growth during the microgel collapse. Though both the disordered and the regular networks exhibit a similar early growth of the domains, an acceleration is observed in the regular network at the late stage of the collapse. Similar trends are found for the dynamic correlations coupled to the domain growth. As a consequence, the fast late processes for the domain growth and the dynamic correlations in the regular network are compensated, and the dynamic correlations follow a power-law dependence on the growing length scale that is independent of the microgel microstructure.

Influence of reversible cross-link coordination on the mechanical behavior of a linear polymer chain

In this work, we investigate the effect of the coordination of cross-links (i.e., the number of monomers participating in one cross-link) on the mechanical performance of a single polymeric chain. The framework provided by the reactive empirical bond order potential is used to generically describe the ability of certain monomers to form cross-links of different coordination. A systematic investigation of the influence of the coordination of cross-links on the mechanical properties of single polymeric chains is presented by comparing systems that contain cross-links in the classical form between two monomers (dimer) and such where the cross-links are formed by three monomers (trimer). The results show that the mechanical performance crucially depends on the coordination of cross-links. The overall shape of the load-displacement curves as well as mechanical parameters like stiffness, strength and work-to-straighten the molecule are different for the different systems. While the load-displacement curve shows an overall more continuous shape for the system containing trimers compared to the system including dimers only, the mechanical parameters are consistently lower for the first system. On the other hand, in contrast to the dimer case a trimer remains stable upon detachment of one of the monomers and the bonds are more mobile. This will be of importance in the case of fiber bundles, where the loading situation is even more complicated than in the single chain system due to the presence of inter-chain cross-links.

Mechanical and Thermomechanical Characterization of Glassy Thermoplastics with Intrachain Cross-Links

The mechanical properties of an amorphous polymer are a consequence of the inter- and intramolecular interactions which are typically similar. Yet, polymers can be made with covalent intramolecular cross-links, leading to stronger intramolecular interactions. Here, a study on the effect of this intramolecular cross-linking on the mechanical properties of a glassy polymer is shown. A linear poly(methyl methacrylate) with defined size was cross-linked at different ratios and assembled into solid samples by solvent casting. Mechanical testing indicates that intramolecular cross-linking does not affect the mechanical properties at the elastic region but does influence these properties at the plastic region. Interestingly, intramolecular cross-linking leads to different effects than “regular” interchain cross-linking. The results are consistent with a reduction in chain entanglement, reducing toughness and to a lesser extent strength.

Dual-Gated Chain Shattering Based on Light Responsive Benzophenones and Thermally Responsive Diels–Alder Linkages

We exploit the light-adaptive characteristics of benzophenone (BP) to introduce a chain-shattering degradation mechanism triggered by light (λmax = 365 nm, 36 W). Incorporated in every repeat unit via a step-growth polymerization of AA- and BB-type difunctional monomers entailing thermally reversible hetero-Diels–Alder (HDA) linkages, the benzophenone functional group enables the disassembly of the on-demand degradable polymers within a few hours to small molecules. Specifically, the benzophenone unit is photoactivated to reversibly generate a biradicaloid triplet state on each monomer moiety, in which the radicals can recombine in an interchain cross-linking reaction or undergo a reduction process, the latter one being key for the disassembly. The newly formed hydroxyl functionality in the ortho-position to the ester bond induces the chain-shattering process via a subsequent lactonization reaction. The polymerization and the light-triggered degradation were assessed in detail by size-exclusion chromatogr...

Fabrication and characterization of hydrothermal cross-linked chitosan porous scaffolds for cartilage tissue engineering applications

The use of various chemical cross-linking agents for the improvement of scaffolds physical and mechanical properties is a common practical method, which is limited by cytotoxicity effects. Due to exerting contract type forces, chondrocytes are known to implement shrinkage on the tissue engineered constructs, which can be avoided by the scaffold cross-linking. In the this research, chitosan scaffolds are cross-linked with hydrothermal treatment with autoclave sterilization time of 0, 10, 20 and 30min, to avoid the application of the traditional chemical toxic materials. The optimization studies with gel content and crosslink density measurements indicate that for 20min sterilization time, the gel content approaches to ~80%. The scaffolds are fully characterized by the conventional techniques such as SEM, porosity and permeability, XRD, compression, thermal analysis and dynamic mechanical thermal analysis (DMTA). FT-IR studies shows that autoclave inter-chain cross-linking reduces the amine group absorption at 1560cm−1 and increase the absorption of N-acetylated groups at 1629cm−1. It is anticipated, that this observation evidenced by chitosan scaffold browning upon autoclave cross-linking is an indication of the familiar maillard reaction between amine moieties and carbonyl groups. The biodegradation rate analysis shows that chitosan scaffolds with lower concentrations, possess suitable degradation rate for cartilage tissue engineering applications. In addition, cytotoxicity analysis shows that fabricated scaffolds are biocompatible. The human articular chondrocytes seeding into 3D cross-linked scaffolds shows a higher viability and proliferation in comparison with the uncross-linked samples and 2D controls. Investigation of cell morphology on the scaffolds by SEM, shows a more spherical morphology of chondrocytes on the cross-linked scaffolds for 21days of in vitro culture.

The interchain disulfide cross-linking of tropomyosin alters its regulatory properties and interaction with actin filament

Tropomyosin (Tpm) is an α-helical coiled-coil actin-binding protein that plays a key role in the Ca2+-regulated contraction of striated muscles. Two chains of Tpm can be cross-linked by formation of a disulfide bond between Cys-190 residues. Normally, the SH-groups of these residues in cardiac muscle are in reduced state but in heart pathologies the interchain cross-linking of Tpm was shown to occur. Previous studies have shown that this cross-linking increases the thermal stability of the C-terminal part of the Tpm molecule. However it was unclear how this affects its functional properties. In the current work, we studied functional features of cross-linked Tpm at the level of isolated proteins. The results have shown that the cross-linking greatly decreases affinity of Tpm for F-actin and stability of the Tpm–F-actin complex. It also increases sliding velocity of regulated thin filaments in an in vitro motility assay. This last effect was mostly pronounced when cardiac isoforms of myosin and troponin were used instead of skeletal ones. The results indicate that cross-linking significantly affects properties of Tpm and actin-myosin interaction and can explain, at least partly, the role of the interchain disulfide cross-linking of cardiac Tpm in human heart diseases.

Controlling the polymer-nanolayer architecture on anion-exchange membrane adsorbers via surface-initiated atom transfer radical polymerization

The immobilization of a polymer-nanolayer containing ligand sites is a widely used approach to increase the binding capacity of membrane adsorbers. In this work strong anion-exchange membrane adsorbers were produced via surface-initiated atom transfer radical polymerization (SI-ATRP) using a monomer bearing a quaternary amine group (Q-type). Additionally the architecture of the polymer-nanolayer has been controlled with respect to the length and density of the grafted polymer chains and in terms of ligand density and interchain crosslinking degree. The influence of these architecture parameters on the membrane permeability and the static binding capacity towards bovine serum albumin (BSA) as a model protein has been investigated. It could be shown that these parameters have a major impact on the performance of the produced membrane adsorbers. While the chain-length and –density significantly increase the binding capacity, a decrease in permeability is observed. The interchain crosslinking degree and a reduction of the ligand density increase the permeability, but simultaneously the static binding capacity is slightly diminished. A well-chosen combination of these architecture parameters can produce membrane adsorbers with static binding capacities >100mg/mL membrane volume (MV) while still maintaining a specific permeability >40mL/(min·cm2·bar), far superior to commercially available products.

Ion Dynamics and Mechanical Properties of Sulfonated Polybenzimidazole Membranes for High-Temperature Proton Exchange Membrane Fuel Cells

Polybenzimidazole (PBI)-based membranes are one of the systems of choice for polymer electrolyte fuel cells. Monomer sulphonation is one of the strategies suggested to improve proton transport in these membranes. We report a NMR and dynamic mechanical study aiming to investigate the effect of the sulphonation on the proton dynamics and the mechanical properties of the membranes. The analyses of 1H self-diffusion coefficients and 1H and 31P spectra versus temperature show that sulphonation causes the formation of interchain cross-links, which involve phosphoric acid molecules and the sulfonic groups. This, in turn, reduces the proton mobility and, consequently, the ionic conductivity. The increase of the membrane stiffness with sulphonation is confirmed by dynamic mechanical analysis through the behavior of the storage modulus.

Electron beam cross-linking of EVA/TPU blends

Ethylene vinyl acetate (EVA) copolymer and thermoplastic polyurethane (TPU) with different blending ratios were melt mixed in an internal mixer. The blends were then exposed to electron beam (EB) irradiation with different doses of 50, 100, 150, 200 and 250 kGy. FTIR spectroscopy and dynamic mechanical thermal analysis (DMTA) were used to investigate the effect of cross-linking and blending ratio on chemical structure as well as solid state viscoelastic properties of the blends. FTIR spectroscopy showed interchain cross-linking during melt blending and also radiation cross-linking during solid state irradiation. Observation of one damping peak for blends at almost all blending ratios was an indication of miscibility of these blends. The results indicated formation of interchain cross-linking stabilised with exposure to EB irradiation. Mechanical properties of the blends were investigated via stress–strain curves. Modulus showed a monotonic increasing trend with the radiation dose, but tensile strength and elongation at break were initially increased and then decreased with increasing radiation dose. This was attributed to two competing parallel factors of strain induced crystallisation and degree of cross-linking.

Enhanced plasma factor VIII activity in mice via cysteine mutation using dual vectors

Hemophilia A is caused by a genetic mutation in coagulation factor VIII (FVIII) gene and gene therapy is considered to be a promising strategy for its treatment. We recently demonstrated that co-delivery of two vectors expressing M662C mutated heavy and D1828C mutated light chain genes of B-domain-deleted coagulation factor VIII (BDD-FVIII) leads to inter-chain disulfide cross-linking and improved heavy chain secretion in vitro. In this study, co-injection of both M662C and D1828C mutated BDD-FVIII gene expression vectors into mice resulted in increased heavy chain secretion and coagulation activity in plasma in vivo. Approximately (239 ± 56) ng mL(-1) above endogenous levels of transgenic FVIII heavy chain was found in mouse plasma using a chain-specific ELISA. For FVIII coagulation activity, approximately (1.09 ± 0.25) IU mL(-1) above endogenous levels were detected in co-injected transgenic mouse plasma using a chromogenic assay. These data demonstrate that inter-chain disulfide bonds likely increase heavy chain secretion and coagulation activity in the plasma of transgenic mice with an improved efficacy of a dual-vector delivery of BDD-FVIII gene. These findings support our ongoing efforts to develop a gene therapy for hemophilia A treatment using dual-AAV vectors.

Deoxyguanosine forms a bis-adduct with E,E-muconaldehyde, an oxidative metabolite of benzene: implications for the carcinogenicity of benzene.

Benzene is employed in large quantities in the chemical industry and is an ubiquitous contaminant in the environment. There is strong epidemiological evidence that benzene exposure induces hematopoietic malignancies, especially acute myeloid leukemia, in humans, but the chemical mechanisms remain obscure. E,E-Muconaldehyde is one of the products of metabolic oxidation of benzene. This paper explores the proposition that E,E-muconaldehyde is capable of forming Gua-Gua cross-links. If formed in DNA, the replication and repair of such cross-links might introduce structural defects that could be the origin of the carcinogenicity. We have investigated the reaction of E,E-muconaldehyde with dGuo and found that the reaction yields two pairs of interconverting diastereomers of a novel heptacyclic bis-adduct having a spiro ring system linking the two Gua residues. The structures of the four diastereomers have been established by NMR spectroscopy and their absolute configurations by comparison of CD spectra with those of model compounds having known configurations. The final two steps in the formation of the bis-nucleoside (5-ring → 6-ring → 7-ring) have significant reversibility, which is the basis for the observed epimerization. The 6-ring precursor was trapped from the equilibrating mixture by reduction with NaBH(4). The anti relationship of the two Gua residues in the heptacyclic bis-adduct precludes it from being formed in B DNA, but the 6-ring precursor could readily be accommodated as an interchain or intrachain cross-link. It should be possible to form similar cross-links of dCyt, dAdo, the ε-amino group of lysine, the imidazole NH of histidine, and N termini of peptides with the dGuo-muconaldehyde monoadduct.

Emergence of Chiral Environments by Effect of Flows: The Case of an Ionic Oligomer and Congo Red Dye

Mechanical chiral induction: In aqueous solutions of a cationic oligomer that forms interchain cross-linking through non-covalent interactions, chiral regions can be obtained reversibly by stirring flows. The chiral induction upon an achiral molecule (Congo Red dye) was demonstrated by Mueller matrix spectroscopy analysis of the optical polarization properties. Shown here is the true CD image of a stirred solution, clockwise (top) and counterclockwise (bottom), of compound 1. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Extraction and isolation of type I, III and V collagens and their SDS-PAGE analyses

Type I, III and V collagens were extracted from bovine dermis and cornea by using pepsin treatment in acetic acid solution, followed by salt precipitation and dialysis, to purify and isolate each type of collagens. The preparation process was analyzed by using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). A reducing agent, 2-mercaptoethanol, was used to remove disulfide bonds and analyze the structure of the bonds involved between α chains in some types of collagens. The use of delayed reducing methods resulted in the difference between α1(III) and α 1(I) chains in a mixture containing type I and III collagens. The structure of disulfide bonds among α chains exists potentially in type V collagen prepared from the pepsin-treatment extraction at 4 °C, which differs from type III collagen in relation to the locations of disulfide bonds. Compared with pepsin-treated collagen at 4 °C, the relative molecular weights of α1(V) and α2(V) chains treated at room temperature decrease by 4.6% and 6.0%, respectively. It is concluded that type I, III and V collagens can be prepared from bovine dermis and cornea by the use of pepsin treatment, salt precipitation and dialysis. The interchain disulfide bonds lie potentially near the edges of termini of type V collagen molecules in extracellular matrix, and a small number of interchain crosslinks exist in type V collagen.

Modulating mechanical properties of self-assembled polymer networks by multi-functional complementary hydrogen bonding

The mechanical properties of reversible polymer networks have been modulated successfully at room temperature with a high degree of control over a large magnitude exclusively by altering the complementary hydrogen bonding interactions used for the inter-chain crosslinking process. For these studies, norbornene-based copolymers have been synthesized with multiple functional side-chains that offer different hydrogen bonding motifs. By adding small molecule crosslinking agents with complementary motifs to solutions of these copolymers, self-assembled polymer networks with tunable mechanical properties were obtained. The hydrogen bonding motifs utilized in this study are based on thymine/2,4-diaminotriazine and cyanuric acid/Hamilton wedge pairs. It was found that the mechanical properties of the self-assembled polymer networks strongly depend upon the type of hydrogen bonding motif used for the inter-chain crosslinking as well as the concentration of crosslinking agent. We were able to modulate the rheological properties of the networks from highly viscous to highly elastic and vary the dynamic moduli over five orders of magnitude at room temperature. This degree of control over the network's mechanical properties was achieved without changing the copolymer backbone architecture. Finally, competitive hydrogen bonding of various motifs was used to de-crosslink and re-crosslink the network at room temperature through the selective addition of various crosslinking agents. In addition to the more common thermal responsiveness of hydrogen bonded networks, competitive binding offers an additional parameter to control the mechanical properties of the self-assembled polymer networks at ambient temperature.

DNA cross‐link induced by trans‐4‐hydroxynonenal

Trans-4-Hydroxynonenal (HNE) is a peroxidation product of omega-6 polyunsaturated fatty acids. Michael addition of HNE to deoxyguanosine yields four diastereomeric 1,N(2)-dG adducts. The adduct of (6S,8R,11S) stereochemistry forms interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence. It has been compared with the (6R,8S,11R) adduct, incorporated into 5'-d(GCTAGCXAGTCC)-3' . 5'-d(GGACTCGCTAGC)-3', containing the 5'-CpG-3' sequence (X = HNE-dG). Both adducts rearrange in DNA to N(2)-dG aldehydes. These aldehydes exist in equilibrium with diastereomeric cyclic hemiacetals, in which the latter predominate at equilibrium. These cyclic hemiacetals mask the aldehydes, explaining why DNA cross-linking is slow compared to related 1,N(2)-dG adducts formed by acrolein and crotonaldehyde. Both the (6S,8R,11S) and (6R,8S,11R) cyclic hemiacetals are located within the minor groove. However, the (6S,8R,11S) cyclic hemiacetal orients in the 5'-direction, while the (6R,8S,11R) cyclic hemiacetal orients in the 3'-direction. The conformations of the diastereomeric N(2)-dG aldehydes, which are the reactive species involved in DNA cross-link formation, have been calculated using molecular mechanics methods. The (6S,8R,11S) aldehyde orients in the 5'-direction, while the (6R,8S,11R) aldehyde orients in the 3'-direction. This suggests a kinetic basis to explain, in part, why the (6S,8R,11S) HNE adduct forms interchain cross-links in the 5'-CpG-3' sequence, whereas (6R,8S,11R) HNE adduct does not. The presence of these cross-links in vivo is anticipated to interfere with DNA replication and transcription, thereby contributing to the etiology of human disease.