Sharma Shivangi, Singh Vishal, Biswas Parbati
Department of Chemistry, University of Delhi, Delhi 110007, India.
ACS Phys Chem Au. 2022 Apr 26;2(4):353-363. doi: 10.1021/acsphyschemau.1c00056. eCollection 2022 Jul 27.
The conformational transitions of the adenosine deaminase A-riboswitch aptamer both with and without ligand binding are investigated within the tenets of the generalized Langevin equation in a complex viscoelastic cellular environment. Steered molecular dynamics (SMD) simulations are performed to evaluate and compare the results of the first passage times (FPTs) with those obtained from the theory for the unfold and fold transitions of the aptamer. The results of the distribution of Kramers's FPT reveal that the unfold-fold transitions are faster and hence more probable as compared to the fold-unfold transitions of the riboswitch aptamer for both ligand-bound and -unbound states. The transition path time is lower than Kramers's FPT for the riboswitch aptamer as the transition path times for the unfold-fold transition of both without and with ligand binding are insensitive to the details of the exact mechanism of the transition events. However, Kramers's FPTs show varied distributions which correspond to different transition pathways, unlike the transition path times. The mean FPT increases with an increase in the complexity of the cellular environment. The results of Kramers's FPT, transition path time distribution, and mean FPT obtained from our calculations qualitatively match with those obtained from the SMD simulations. Analytically derived values of the mean transition path time show good quantitative agreement with those estimated from the single-molecule force spectroscopy experiments for higher barrier heights.
在复杂的粘弹性细胞环境中，依据广义朗之万方程的原理，研究了腺苷脱氨酶A-核糖开关适体在结合配体和未结合配体情况下的构象转变。进行了引导分子动力学（SMD）模拟，以评估并比较首次通过时间（FPTs）的结果与从适体展开和折叠转变理论获得的结果。克莱默斯FPT分布的结果表明，与核糖开关适体在配体结合和未结合状态下的折叠-展开转变相比，展开-折叠转变更快，因此更有可能发生。对于核糖开关适体，转变路径时间低于克莱默斯FPT，因为在未结合配体和结合配体情况下展开-折叠转变的转变路径时间对转变事件的确切机制细节不敏感。然而，与转变路径时间不同，克莱默斯FPT显示出对应于不同转变途径的不同分布。平均FPT随着细胞环境复杂性的增加而增加。我们计算得到的克莱默斯FPT、转变路径时间分布和平均FPT结果在定性上与SMD模拟得到的结果相匹配。对于较高的势垒高度，平均转变路径时间的解析推导值与从单分子力谱实验估计的值显示出良好的定量一致性。
