THEORETICAL INSIGHTS INTO THE RELATIONSHIP BETWEEN ELECTRONIC STRUCTURE AND SIGNALING IN ANTIBODY-ANTIGEN SYSTEMS

Biological macromolecular interactions have been understood through classic induced-fit mechanisms. However, recent advances in quantum biology suggest that electron transfer and electrostatic fields can play critical roles in biological recognition and signaling. It is known that, in enzymes, the frontier molecular orbitals (MOs) surrounding the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) are localized at the active site, where they are required for catalysis (Fukushima et al., 2008, 10.1002/prot.21865). In the antigen-antibody system, on the other hand, results from our group have demonstrated that MOs in this frontier range are delocalized across the entire extent of the complex formed by the antigen and its antigen-binding fragment (Fab), and also demonstrated extensive electric dipoles (500 to 900 D) conserved longitudinally along this fragment. At various protein interfaces (including antibody-antigen complexes), the group observed intermolecular electron density that could mediate electron transfer. This finding supports previous literature showing that amino acid pairs form intermolecular electron-transfer complexes in thousands of protein systems (Wang, et al., 2018, 10.1021/acsomega.8b00336). In this work, we investigated the electronic structure and electrostatic properties of antigen-antibody complexes. Quantum calculations on electronic structure of Fab region (PDB ID: 1IQW), using GFN2-xTB method, were performed to map the frontier molecular orbitals, from 1 eV below HOMO to 1 eV above LUMO. Our results revealed a narrow energy gap of 0.0088 eV (0.2029 kcal/mol) between the HOMO and LUMO, which is lower than the thermal energy at room temperature (0.59 kcal/mol). This gap is also smaller than the lower limit (0.1 eV) observed in organic semiconductors (Morab, et al., 2023, 10.3390/coatings13091657). The combination of the extensive delocalization of MOs with this small energy gap, allows for a comparison between Fab structure and organic semiconductors. In this hypothesized semiconductor-like framework, a perturbation of the electronic structure - such as that caused by antigen binding - could promote electron transfer by thermal excitation. Furthermore, the extensive macrodipole within Fab region may act as an electric potential gradient, pointing to a possible mechanism for electronic signaling.

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