Structural insights and predictive modelling of a novel anti-HER2 scFv and Leptulipin: a newly designed immunotoxin protein for HER2 positive cancers

Targeted therapy is one crucial therapeutic approach frequently employed in cancer treatment. In almost 30% of human breast cancers, a transmembrane tyrosine kinase receptor named the HER2 (human epidermal growth factor receptor 2) is overexpressed, establishing HER-2 as a promising target for cancer treatment. The goal of the current work is to computationally design and analyze a new chimeric protein that could selectively target HER2-positive breast cancer cells based on a single polypeptide chain variable fragment and leptulipin (an anticancer peptide) fusion. After the computational joining of the secondary structure, 3D modeling, quality validation, physicochemical properties, docking, interaction analysis, MD simulation, and energy calculations were performed using various computational tools and online servers. The most precise predicted chimeric protein model was docked to the HER-2 receptor using ClusPro 2.0, which revealed a significant number of hydrogen bonds and salt bridges reflecting the fusion protein's quality, validity, interaction, and stability. These results were further supported by MD simulation on the Desmond Schrodinger module, which predicted a stable docked complex. This was also evident by principal component analysis and the negative energy value of MM/PBSA. These comprehensive in silico analyses, coupled with a high predicted expression value of 0.94 in <i>E. coli</i> by the SOLUPROT, collectively highlight the potential of fusion protein as a potent therapeutic agent against breast cancer and open a potential avenue for targeted cancer therapy and provide a groundwork for in vitro and in vivo validation that might lead to clinical implication.