Institute of Molecular Biology and Pathology, CNR c/o Dep. Chemistry, University of Rome, Sapienza, P.le A. Moro 5, 00185 Rome, Italy.
Institute of Biostructures and Bioimaging, CNR, Via Pietro Castellino 111, 80131 Naples, Italy.
J Chem Inf Model. 2022 Aug 22;62(16):3874-3884. doi: 10.1021/acs.jcim.2c00727. Epub 2022 Aug 5.
Tetrameric hemoglobins (Hbs) are prototypal systems for studies aimed at unveiling basic structure-function relationships as well as investigating the molecular/structural basis of adaptation of living organisms to extreme conditions. However, a chronological analysis of decade-long studies conducted on Hbs is illuminating on the difficulties associated with the attempts of gaining functional insights from static structures. Here, we applied molecular dynamics (MD) simulations to explore the functional transition from the T to the R state of the hemoglobin of the Antarctic fish (HbTb). Our study clearly demonstrates the ability of the MD technique to accurately describe the transition of HbTb from the T to R-like states, as shown by a number of global and local structural indicators. A comparative analysis of the structural states that HbTb assumes in the simulations with those detected in previous MD analyses conducted on HbA (human Hb) highlights interesting analogies (similarity of the transition pathway) and differences (distinct population of intermediate states). In particular, the ability of HbTb to significantly populate intermediate states along the functional pathway explains the observed propensity of this protein to assume these structures in the crystalline state. It also explains some functional data reported on the protein that indicate the occurrence of other functional states in addition to the canonical R and T ones. These findings are in line with the emerging idea that the classical two-state view underlying tetrameric Hb functionality is probably an oversimplification and that other structural states play important roles in these proteins. The ability of MD simulations to accurately describe the functional pathway in tetrameric Hbs suggests that this approach may be effectively applied to unravel the molecular and structural basis of Hbs exhibiting peculiar functional properties as a consequence of the environmental adaptation of the host organism.
四聚体血红蛋白（Hb）是研究基本结构-功能关系以及研究生物适应极端条件的分子/结构基础的典型系统。然而，对长达十年的 Hb 研究进行的时间分析清楚地表明了从静态结构中获得功能见解的尝试所面临的困难。在这里，我们应用分子动力学（MD）模拟来探索南极鱼血红蛋白（HbTb）从 T 态到 R 态的功能转变。我们的研究清楚地表明，MD 技术能够准确地描述 HbTb 从 T 态到 R 样态的转变，这可以通过许多全局和局部结构指标来证明。对 HbTb 在模拟中所采用的结构状态与以前在 HbA（人 Hb）上进行的 MD 分析中检测到的结构状态进行比较分析，突出了有趣的相似性（转变途径的相似性）和差异（中间状态的不同群体）。特别是，HbTb 能够沿着功能途径显著地占据中间状态，这解释了观察到的该蛋白在晶体状态下呈现这些结构的倾向。它还解释了一些关于该蛋白的功能数据，这些数据表明除了经典的 R 和 T 态之外，还存在其他功能态。这些发现与新兴的观点一致，即四聚体 Hb 功能的经典两态观点可能过于简单化，并且其他结构状态在这些蛋白中起着重要作用。MD 模拟能够准确地描述四聚体 Hb 中的功能途径，这表明该方法可以有效地应用于揭示由于宿主生物的环境适应而表现出特殊功能特性的 Hb 的分子和结构基础。
