极端中和表型HIV包膜蛋白gp120的高温分子动力学模拟研究

作为HIV侵染细胞的蛋白质机器,包膜蛋白gp120利用序列变异和结构柔性等策略逃避宿主免疫识别,是病毒呈现出不同中和表型的主要原因.尽管HIV中和表型的分子机制已被初步探索,但其热力学相关的分子基础仍待进一步阐明.本研究利用同源模建的方法构建了极端中和表型HIV毒株(中和抵抗毒株H061.14与中和敏感毒株R2)的gp120结构模型,在逐渐升高的温度梯度下进行了高温分子动力学模拟,以研究二者在结构稳定性、解折叠和构象柔性上的差异.结果表明,HIV中和表型与gp120的热力学性质呈正相关,与解折叠程度无必然关联.各温度下gp120的结构偏差、天然接触含量、构象群体分布,以及单残基柔性的比较清楚地说明,中和敏感比中和抵抗gp120表现出更大的结构偏差、更多的构象状态和更高的构象柔性,但两者具有相似的解折叠程度.由极端中和表型HIV包膜蛋白gp120显著不同的热力学性质可以推断,HIV很可能利用gp120的热力学性质来调节其构象,进而平衡病毒侵染和免疫逃避之间的矛盾.我们的研究不仅揭示了极端中和表型HIV包膜蛋白gp120的在构象柔性和结构稳定性上的差异,同时还从高温解折叠热力学的角度明确了...

High temperature molecular dynamics simulation study on the envelope protein gp120 of HIV strains with extreme neutralization phenotype

As the protein machine for HIV infecting cells, the envelope protein gp120 exploits strategies such as sequence variation and structural flexibility to evade host immune recognition, which is the main cause of the different neutralization phenotypes of HIV. Although the molecular mechanism of HIV neutralization phenotype has been initially explored, the molecular basis related to its thermodynamics still needs to be further elucidated. In this study, the method of homology modeling was employed to construct the gp120 structural models from HIV strains with extreme neutralization phenotype (neutralization-resistant strain H061.14 and neutralization-sensitive strain R2), and the high-temperature molecular dynamics simulations were performed under a gradually increasing temperature gradient to investigate the differences in structural stability, unfolding and conformational flexibility between these two phenotypic gp120. Our results indicate that the HIV neutralization phenotype is positively correlated with the thermodynamic properties of gp120, but not necessarily related to the degree of unfolding. The comparative analysis of structural deviations, native contact content, conformational population distribution, and per-residue flexibility of gp120 at various temperatures clearly indicate that neutralization sensitive gp120 exhibits greater structural deviation, more conformational states, and higher conformational flexibility than neutralization resistance, but both have a similar degree of unfolding. It can be inferred from the remarkable different thermodynamic properties of envelope protein gp120 from HIV strains with extreme neutralization phenotype that HIV is likely to use the thermodynamic properties of gp120 to adjust its conformation to balance the contradiction between virus infection and immune evasion. Our research not only reveals the differences in conformational flexibility and structural stability of gp120 from HIV strains with extreme neutralization phenotype, but also deciphers the molecular basis underlying the extreme neutralization phenotype of HIV from the perspective of high temperature unfolding thermodynamics of gp120.