مطالعه اثر كپ‌دار كردن پپتيد بر ميل اتصالي آن بر روي اهداف پروتئيني

Peptides, as short chains of amino acids, play a fundamental role in regulating biological processes an‎d in the development of targeted therapeutics. Despite their valuable advantages, such as high specificity, favorable biocompatibility, an‎d structural modifiability, several challenges—including instability in biological environments, short half-life, an‎d susceptibility to enzymatic degradation—limit their direct therapeutic application. One of the key strategies to overcome these limitations is N- an‎d C-terminal capping, which can significantly influence the electrical charge, secondary structure, receptor binding affinity, conformational stability, resistance to enzymatic degradation, an‎d membrane permeability of peptides. By forming more stable hydrogen bonds an‎d reducing terminal flexibility, this process enhances self-assembly an‎d improves binding efficiency in the design of nanostructures an‎d peptide-based drugs. In this study, to investigate the effect of terminal capping on the binding affinity of peptides to the receptor, a series of selec‎ted peptide sequences were first modeled in their uncapped form an‎d then subjected to terminal capping. Molecular docking was performed using AutoDock an‎d Vina software, an‎d binding energy, interaction types, an‎d structural stability of the peptide–receptor complexes were eva‎luated. To analyze the trend of changes with increasing sequence length, a stepwise construction approach was employed, in which the structures were gradually extended from dipeptides to heptapeptides, followed by redocking at each stage. This approach enabled a detailed eva‎luation of the effect of chain length extension an‎d the role of capping at each step. The results showed that uncapped peptides, although exhibiting favorable binding energies at certain lengths, displayed greater structural fluctuations an‎d less stable binding behavior. In contrast, capped peptides demonstrated a more consistent energy profile, stronger binding affinity, an‎d more targeted hydrogen-bond interactions with the active site of the receptor. These findings indicate that capping strengthens key interactions, reduces rotational freedom, an‎d consequently enhances binding quality. Overall, the results confirm the importance of capping in improving binding capability, increasing molecular half-life, reducing enzymatic degradation, an‎d enhancing the therapeutic efficiency of peptides. Based on these findings, it is recommended that LigPlot interaction maps an‎d molecular dynamics simulations be employed in future studies to achieve a deeper understan‎ding of the binding mechanism an‎d to facilitate the optimal design of peptide-based therapeutics.

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