Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa.
Renewable Energy Programme, Federal Ministry of Environment, 444 Aguiyi Ironsi Way, Maitama, Abuja 904101, Nigeria.
Molecules. 2022 Mar 2;27(5):1640. doi: 10.3390/molecules27051640.
The H7N9 virus attaches itself to the human cell receptor protein containing the polysaccharide that terminates with sialic acid. The mutation of neuraminidase at residue E119 has been explored experimentally. However, there is no adequate information on the substitution with E119V in peramivir at the intermolecular level. Therefore, a good knowledge of the interatomic interactions is a prerequisite in understanding its transmission mode and subsequent effective inhibitions of the sialic acid receptor cleavage by neuraminidase. Herein, we investigated the mechanism and dynamism on the susceptibility of the E119V mutation on the peramivir-neuraminidase complex relative to the wildtype complex at the intermolecular level. This study aims to investigate the impact of the 119V substitution on the neuraminidase-peramivir complex and unveil the residues responsible for the complex conformations. We employed molecular dynamic (MD) simulations and extensive post-MD analyses in the study. These extensive computational investigations were carried out on the wildtype and the E119V mutant complex of the protein for holistic insights in unveiling the effects of this mutation on the binding affinity and the conformational terrain of peramivir-neuraminidase E119V mutation. The calculated total binding energy (ΔG) for the peramivir wildtype is -49.09 ± 0.13 kcal/mol, while the E119V mutant is -58.55 ± 0.15 kcal/mol. The increase in binding energy (9.46 kcal/mol) is consistent with other post-MD analyses results, confirming that E119V substitution confers a higher degree of stability on the protein complex. This study promises to proffer contributory insight and additional knowledge that would enhance future drug designs and help in the fight targeted at controlling the avian influenza H7N9 virus. Therefore, we suggest that experimentalists collaborate with computational chemists for all investigations of this topic, as we have done in our previous studies.
H7N9 病毒附着在含有以唾液酸结尾的多糖的人类细胞受体蛋白上。实验探索了神经氨酸酶残基 E119 的突变。然而，在分子间水平上，关于帕拉米韦中 E119V 的取代，没有足够的信息。因此，了解原子间相互作用是理解其传播模式和随后有效抑制神经氨酸酶对唾液酸受体切割的先决条件。在本文中，我们在分子间水平上研究了 E119V 突变对帕拉米韦-神经氨酸酶复合物相对于野生型复合物的敏感性的机制和动态。本研究旨在研究 119V 取代对神经氨酸酶-帕拉米韦复合物的影响，并揭示负责复合物构象的残基。我们在研究中使用了分子动力学 (MD) 模拟和广泛的 MD 后分析。这些广泛的计算研究是在野生型和 E119V 突变体蛋白复合物上进行的，旨在全面了解这种突变对帕拉米韦-神经氨酸酶 E119V 突变结合亲和力和构象地形的影响。帕拉米韦野生型的总结合能 (ΔG) 计算值为-49.09 ± 0.13 kcal/mol，而 E119V 突变体为-58.55 ± 0.15 kcal/mol。结合能的增加 (9.46 kcal/mol) 与其他 MD 后分析结果一致，证实 E119V 取代赋予蛋白质复合物更高的稳定性。这项研究有望提供有价值的见解和额外的知识，以增强未来的药物设计，并有助于针对控制禽流感 H7N9 病毒的目标。因此，我们建议实验家和计算化学家在所有对此主题的研究中进行合作，就像我们在之前的研究中所做的那样。
