Revealing the molecular interactions of aptamers that specifically bind to the extracellular domain of HER2 cancer biomarker protein: An in silico assessment

Single-stranded (ss) oligonucleotide aptamers are emerging as the promising substitutes for monoclonal antibodies because of their low production cost and good batch-to-batch consistency. Aptamers vividly bind to a variety of cellular targets and alter their functions with a remarkable degree of specificities. In this study, the positive clones of human epidermal growth factor receptor 2 (HER2) specific binding ssDNA aptamers which were previously identified by in vitro Systematic Evolution of Ligands by EXponential enrichment (SELEX) process, hitherto lacking the putative binding site information and residues crucial for aptamer recognition are studied. Primarily, four putative DNA binding regions present on the HER2 extracellular domain (ECD) were identified using prediction servers and electrostatic potential maps, which were further exploited to delineate the aptamer binding features. Molecular docking and molecular dynamics (MD) simulations revealed stable binding nature of three aptamers (H2>H1>H6), which chose Site 2a as preferred binding site present on the HER2(ECD) protein. Furthermore, amino acid residues viz. Asn37, Gln59, Arg81-Gln84, Asp88, and Lys128 of Site 2a were found to be crucial for high-affinity binding. This knowledge can be utilized as a benchmark for the future studies, in search for better and highly specific anti-HER2 aptamers as cancer therapeutics or as diagnostic agents.