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 Trematomus bernacchii (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.

中文翻译：

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脊椎动物血红蛋白功能转变的原子级观点：以南极鱼 Hbs 为例

四聚体血红蛋白 (Hbs) 是用于研究的原型系统，旨在揭示基本的结构-功能关系以及研究生物体适应极端条件的分子/结构基础。然而，对 Hbs 进行的长达十年的研究的时间顺序分析阐明了与尝试从静态结构中获得功能洞察力相关的困难。在这里，我们应用分子动力学 (MD) 模拟来探索南极鱼Trematomus bernacchii血红蛋白从 T 状态到 R 状态的功能转变(HbTb)。我们的研究清楚地证明了 MD 技术能够准确描述 HbTb 从 T 到 R 样状态的转变，如许多全局和局部结构指标所示。HbTb 在模拟中假设的结构状态与之前对 HbA（人类 Hb）进行的 MD 分析中检测到的结构状态的比较分析突出了有趣的类比（过渡途径的相似性）和差异（不同的中间状态群体）。特别是，HbTb 沿功能途径显着填充中间状态的能力解释了观察到的这种蛋白质倾向于将这些结构呈现为结晶状态。它还解释了一些关于蛋白质报告的功能数据，这些数据表明除了典型的 R 和 T 之外还存在其他功能状态。这些发现与新出现的观点一致，即基于四聚体 Hb 功能的经典二态观点可能过于简单化，并且其他结构状态在这些蛋白质中起重要作用。MD 模拟准确描述四聚体 Hbs 中功能途径的能力表明，这种方法可以有效地用于揭示 Hbs 的分子和结构基础，这些 Hbs 表现出由于宿主生物体的环境适应而表现出的特殊功能特性。这些发现与新出现的观点一致，即基于四聚体 Hb 功能的经典二态观点可能过于简单化，并且其他结构状态在这些蛋白质中起重要作用。MD 模拟准确描述四聚体 Hbs 中功能途径的能力表明，这种方法可以有效地用于揭示 Hbs 的分子和结构基础，这些 Hbs 表现出由于宿主生物体的环境适应而表现出的特殊功能特性。这些发现与新出现的观点一致，即基于四聚体 Hb 功能的经典二态观点可能过于简单化，并且其他结构状态在这些蛋白质中起重要作用。MD 模拟准确描述四聚体 Hbs 中功能途径的能力表明，这种方法可以有效地用于揭示 Hbs 的分子和结构基础，这些 Hbs 表现出由于宿主生物体的环境适应而表现出的特殊功能特性。