Hydrogen bond networks determine emergent mechanical and thermodynamic properties across a protein family.
Hydrogen bond networks determine emergent mechanical and thermodynamic properties across a protein family.
复制标题
氢键网络确定蛋白质家族中新兴的机械和热力学特性。
DOI：
10.1186/1752-153x-2-17
复制
发表时间：
2008-08-12
影响因子：
--
通讯作者：
Jacobs, Donald J.
中科院分区：
文献类型：
--
作者：
Livesay, Dennis R.;Huynh, Dang H.;Dallakyan, Sargis;Jacobs, Donald J.
革兰氏阴性细菌使用周质结合蛋白(BPBP)通过周质运输营养物质。尽管已知底物的多样性很大，但该家族的所有成员都有一个共同的折叠，其中包括由保守的铰链分开的两个结构域。铰链允许蛋白质在开放(Apo)和闭合(连接)构象之间循环。蛋白质内部的构象变化依赖于复杂的力学和热力学反应的相互作用，表现为配体结合时热稳定性的增加和灵活性的降低。我们使用距离约束模型(DCM)来量化BPBP家族中热力学稳定性和机械灵活性之间的取舍。定量稳定性/弹性关系(QSFR)很容易评估，因为DCM将机械和热力学属性联系在一起。我们以前已经证明了QSFR在中温/嗜热RNaseH对中温和保守，而观察到的差异表明，不同的热焓-熵机制允许在各自的熔化温度下做出类似的机械响应。我们对热容和自由能的预测显示出BPBP家族的显著多样性。虽然主干灵活性指标大多是保守的，但协作性相关性(远程耦合)也显示出相当大的差异。去除配体后，热容、熔点和机械刚性如预期的那样降低。然而，在分子协作性关联方面发现了显著的差异，这可以用氢键网络的详细性质来解释。整个家族中不平凡的机械和热力学差异是由潜在的氢键网络中的差异解释的。其机制很简单；氢键网络中的变化会导致机械连接属性的改变，从而直接影响固有的灵活性。此外，不同数量的氢键及其强度控制了氢键断裂和重整时能量波动的可能性，从而直接影响热力学性质。因此，这些结果表明，如何从潜在的氢键网络中的细微差异中出现意想不到的巨大差异，特别是在协作性相关性内。这一推论与众所周知的结果一致，即一个家族内的变构反应通常存在显着差异。将氢键网络确定为这些大变化的关键决定因素可能会导致能够预测这种影响的新方法。
Gram-negative bacteria use periplasmic-binding proteins (bPBP) to transport nutrients through the periplasm. Despite immense diversity within the recognized substrates, all members of the family share a common fold that includes two domains that are separated by a conserved hinge. The hinge allows the protein to cycle between open (apo) and closed (ligated) conformations. Conformational changes within the proteins depend on a complex interplay of mechanical and thermodynamic response, which is manifested as an increase in thermal stability and decrease of flexibility upon ligand binding. We use a distance constraint model (DCM) to quantify the give and take between thermodynamic stability and mechanical flexibility across the bPBP family. Quantitative stability/flexibility relationships (QSFR) are readily evaluated because the DCM links mechanical and thermodynamic properties. We have previously demonstrated that QSFR is moderately conserved across a mesophilic/thermophilic RNase H pair, whereas the observed variance indicated that different enthalpy-entropy mechanisms allow similar mechanical response at their respective melting temperatures. Our predictions of heat capacity and free energy show marked diversity across the bPBP family. While backbone flexibility metrics are mostly conserved, cooperativity correlation (long-range couplings) also demonstrate considerable amount of variation. Upon ligand removal, heat capacity, melting point, and mechanical rigidity are, as expected, lowered. Nevertheless, significant differences are found in molecular cooperativity correlations that can be explained by the detailed nature of the hydrogen bond network. Non-trivial mechanical and thermodynamic variation across the family is explained by differences within the underlying H-bond networks. The mechanism is simple; variation within the H-bond networks result in altered mechanical linkage properties that directly affect intrinsic flexibility. Moreover, varying numbers of H-bonds and their strengths control the likelihood for energetic fluctuations as H-bonds break and reform, thus directly affecting thermodynamic properties. Consequently, these results demonstrate how unexpected large differences, especially within cooperativity correlation, emerge from subtle differences within the underlying H-bond network. This inference is consistent with well-known results that show allosteric response within a family generally varies significantly. Identifying the hydrogen bond network as a critical determining factor for these large variances may lead to new methods that can predict such effects.