The hybrid atomistic structure-based model has been validated to be effective in investigation of G-quadruplex folding.In this study,we performed large-scale conventional all-atom simulations to complement the folding...The hybrid atomistic structure-based model has been validated to be effective in investigation of G-quadruplex folding.In this study,we performed large-scale conventional all-atom simulations to complement the folding mechanism of human telomeric sequence Htel24 revealed by a multi-basin hybrid atomistic structure-based model.Firstly,the real time-scale of folding rate,which cannot be obtained from the structure-based simulations,was estimated directly by constructing a Markov state model.The results show that Htel24 may fold as fast as on the order of milliseconds when only considering the competition between the hybrid-1 and hybrid-2 G-quadruplex conformations.Secondly,in comparison with the results of structure-based simulations,more metastable states were identified to participate in the formation of hybrid-1 and hybrid-2 conformations.These findings suggest that coupling the hybrid atomistic structure-based model and the conventional all-atom model can provide more insights into the folding dynamics of DNA G-quadruplex.As a result,the multiscale computational framework adopted in this study may be useful to study complex processes of biomolecules involving large conformational changes.展开更多
文摘目的研究溶液p H变化对抗菌肽LL-37结构的影响。方法利用分子动力学模拟方法,采用GROMACS软件包和OPLS-AA力场,分别在中性和强碱性条件下对LL-37进行模拟,总模拟时间达1微秒,最后对模拟轨迹进行分析处理。结果LL-37在中性环境下具有部分螺旋结构存在,特别是N端部分残基,结构具有较大柔性;在强碱性环境下,螺旋含量增多,抗菌核心区域残基形成螺旋结构的几率明显增大,结构稳定性增强。结论 p H值的增大会促进LL-37螺旋结构的形成,螺旋结构的形成和与膜结合是协同的。N端残基易形成螺旋,然后是抗菌核心区域。LL-37在中性环境下的结构特征与其行使多功能的角色相一致。该研究首次分析了LL-37在中性环境下的结构特征及p H的影响,有助于认识其抗菌机制及新药设计。
基金the National Natural Science Foundation of China(Grant Nos.11504043,61671107,31670727,and 61771093)the Science Foundation of Shandong Province of China(Grant No.ZR2016JL027)+1 种基金the Taishan Young Scholars Program of Shandong Province of China(Grant No.tsqn20161049)the Youth Science and Technology Innovation Plan of Universities in Shandong,China(Grant No.2019KJE007)。
文摘The hybrid atomistic structure-based model has been validated to be effective in investigation of G-quadruplex folding.In this study,we performed large-scale conventional all-atom simulations to complement the folding mechanism of human telomeric sequence Htel24 revealed by a multi-basin hybrid atomistic structure-based model.Firstly,the real time-scale of folding rate,which cannot be obtained from the structure-based simulations,was estimated directly by constructing a Markov state model.The results show that Htel24 may fold as fast as on the order of milliseconds when only considering the competition between the hybrid-1 and hybrid-2 G-quadruplex conformations.Secondly,in comparison with the results of structure-based simulations,more metastable states were identified to participate in the formation of hybrid-1 and hybrid-2 conformations.These findings suggest that coupling the hybrid atomistic structure-based model and the conventional all-atom model can provide more insights into the folding dynamics of DNA G-quadruplex.As a result,the multiscale computational framework adopted in this study may be useful to study complex processes of biomolecules involving large conformational changes.
