Submit Manuscript | http://medcraveonline.com Abbreviations: DOPA, 3,4-dihydroxy phenylalanine; MAPs, mussel adhesive proteins; QM, quantum mechanics; MM, molecular mechanics; PEG, polyethylene glycol; LAMBA, light activated mus- sel-based bio adhesive; DFT, density functional theory; EPR, electron paramagnetic resonance; DCTA, double-crosslinked tissue adhesives; UFF, universal force feld; ONIOM, own n-layer integrated molecular orbital molecular mechanics Introduction Marine mussels adhesive proteins (MAPs) bind to virtually any surface under wet conditions. 1,2 Over the years, extensive efforts have been made to elucidate this remarkable adhesion property because of the wide potential applications of an adhesive that is capable of sticking to wet surfaces. These applications include bonding of tissue in the wet environment inside the body. In Jo et al. 3 suggested biomimetic adhesive materials containing cyanoacryl groups for medical application. 3 Yang and coworkers have introduced an injectable biocompatible biomimetic adhesive for use inside the body. 4 Mussel adhesive protein inspired injectable citrate-based bio- adhesive bone implants have also been developed. 5 In Jeon et al. 6 reported a blue light-activated mussel-based bio-adhesive (LAMBA) which is compatible with the human body and binds strongly in wet conditions. 6 Cross-linking is the keystone to hydrogels. Hydrogel is a three dimensional structure with high water content that is cross- linked together by irreversible chemical bonds. 7 Conventional wound healing such as sutures or staples leads to scar formation. 8 Scar formation makes the body part sensitive which restrict body movement and may cause cancer. 9,10 Cyanoacrylate and fbrin glue are the commercially available tissue adhesive, besides there advantages these tissue adhesives poses risk to many diseases. 11,12 Other potential applications include underwater construction. 13 It is now well known that MAPs contain an unusually high fraction of 3,4-dihydroxyphenylalanine (DOPA). 14‒16 The catechol functionalities (1,2-dihydroxybenzene) of DOPA are believed to anchor MAPs onto surfaces. 17,18 A recent density functional theory (DFT) study has shown that catechol displaces the pre-adsorbed water molecules on a silica surface, and the binding energies and forces involved were calculated. 1 The versatility of mussel adhesion has been attributed to the fact that catechol has both hydroxyls and a phenylene ring which can establish frm adhesion to both polar and non-polar surfaces. 19 Messersmith et al. 20 have developed a tissue adhesive system of four-armed PEG ended with catechol group having strong adhesive strength, low toxicity and excellent wound closure. 21‒24 We note that the adhesion of MAPs requires a relatively slow 1 to 4 hour long 14,25 curing process in which an extensive cross-linking of these MAPs occurs 15,26 The catechol, which is the terminal end of the DOPA molecule, has an oxidized form quinone which is believed to be responsible for the cross-linking with transition metals. 27 However, the exact mechanism of the cross-linking remains elusive, especially at the molecular level. Experimentally, it is found that the transition metal content (e.g. iron, copper and zinc) in the cross linked MAPs reaches up to 100,000 times the levels found naturally in marine water 13,15‒17 Previous studies have speculated that transition metal ions are mainly involved in the protein-protein cross-linking. 15 Lee and coworkers have studied the effect of pH on the rate of curing and bioadhesive properties of dopamine functionalized poly (ethylene glycol) hydrogels. 20 Experimentally, the compression and shear properties of the cross linked MAPs have been estimated by measuring the force required to penetrate a rod through the cross-linked MAPs. 15,16 These studies showed that the greatest degree of curing was produced by Fe 3+ and Mn 3+ among the available biological metal ions examined. 15,16 An electron paramagnetic resonance (EPR) spectroscopic study of the glue produced by mussels revealed a prominent high-spin Fe 3+ signal. Mary et al. 13 also reported that when DOPA-containing protein precursors of mussel glue are cross-linked with Fe 3+ , high-spin Fe 3+ MOJ Biorg Org Chem. 2017;1(6):211‒216. 211 © 2017 Mian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially. Density functional theory study of mussel adhesive protein (l-dopa & catechol) cross-linking Volume 1 Issue 6 - 2017 Shabeer Ahmad Mian, 1 Salem UL Azzam, 1 Gul Rahman, 2 Ejaz Ahmed 3 1 Department of Physics, University of Peshawar, Pakistan 2 Institute of chemical Sciences, University of Peshawar, Pakistan 3 Department of physics, Abdul Wali Khan, Pakistan Correspondence: Shabeer Ahmad Mian, Computational Nanomaterials Science Lab, Department of Physics, University of Peshawar, Pakistan, Email shabeerahmad@uop.edu.pk, shabeerahmad@gmail.com Received: October 30, 2017 | Published: November 30, 2017 Abstract Marine mussel adhesive proteins (MAPs) irreversibly stick to different wet surfaces. Adhesion involves the cross-linking of the MAPs mediated by transition metal ions that make coordination complexes with Catechol. To better understand this cross-linking, the quantum mechanics/molecular mechanics (QM/MM) method was employed to simulate four different transition metal ions, Fe 2+ , Fe 3+ , Cr 3+ and Mn 3+ , forming tris complexes with catechol and with 3, 4-dihydroxy phenylalanine (DOPA) modified polyethylene glycol (PEG) polymer. The binding energy of the metal to the ligand is of special interest. This is the molecular origin of the mechanical properties of cross- linked MAPs. To examine the structures and binding energies, density functional theory calculations were performed for different metal ions that make coordination complexes with a catechol through which polymeric ligand similar to MAPs binds to the metal ions. Among the investigated metal ions, Fe 3+ gives the strongest cross linking, which is in good agreement with experimental data. Keywords: transition metal complex, curing, crosslinking, metal ions, mussels adhesive protein MOJ Bioorganic & Organic Chemistry Research Article Open Access