Enthalpy-entropy compensation and cooperativity as thermodynamic epiphenomena of structural flexibility in ligand-receptor interactions.
Enthalpy-entropy compensation and cooperativity as thermodynamic epiphenomena of structural flexibility in ligand-receptor interactions.
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DOI：
10.1016/j.jmb.2012.01.057
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发表时间：
2012-04-13
影响因子：
5.6
通讯作者：
Gorski, Jack
中科院分区：
文献类型：
--
作者：
Ferrante, Andrea;Gorski, Jack
配体结合在许多生化系统中是一个化学协同过程，其特征在于反应物的构象灵活性。然而，构象熵的贡献的协同连接需要阐明。在这里，我们进行动力学和热力学分析的一个面板上的周期突变的肽，来自流感H3 HA 306 -319，与野生型和突变的HLA-DR相互作用。我们观察到，在一定范围内的肽亲和力，该系统显示等温熵-焓补偿（IEEC）。在配体或受体中加入破坏性突变时测得的构象熵的增量增加在幅度上足以解释实验观察到的自由能减少协同性的缺乏。超过该亲和力范围，未观察到补偿，因此残余相互作用形成稳定复合物的能力以指数方式降低。两者合计，我们的研究结果表明，协同性和IEEC构成的结构波动，伴随着配体/受体复合物的形成在灵活的系统中的热力学副现象。因此，配体结合亲和力预测需要考虑结合能的每个来源如何在基于结构收紧和构象移动性的限制之间的权衡的过程中协同地有助于复合物的折叠和动力学稳定性。
Ligand binding is a thermodynamically cooperative process in many biochemical systems characterized by the conformational flexibility of the reactants. However the contribution of conformational entropy to cooperativity of ligation needs to be elucidated. Here we perform kinetic and thermodynamic analyses on a panel of cycle-mutated peptides, derived from influenza H3 HA306-319, interacting with wild type and a mutant HLA-DR. We observe that within a certain range of peptide affinity, this system shows isothermal entropy-enthalpy compensation (iEEC). The incremental increases in conformational entropy measured as disruptive mutations are added in the ligand or receptor are more than sufficient in magnitude to account for the experimentally observed lack of free energy decrease cooperativity. Beyond this affinity range, compensation is not observed, and therefore the ability of the residual interactions to form a stable complex decreases in an exponential fashion. Taken together, our results indicate that cooperativity and iEEC constitute the thermodynamic epiphenomena of the structural fluctuation that accompanies ligand/receptor complex formation in flexible systems. Therefore, ligand binding affinity prediction needs to consider how each source of binding energy contributes synergistically to the folding and kinetic stability of the complex in a process based on the trade-off between structural tightening and restraint of conformational mobility.
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影响因子：
--
作者：
KRUG, RR;HUNTER, WG;GRIEGER, RA
通讯作者：
GRIEGER, RA
影响因子：
2.9
作者：
Anderson, MW;Gorski, J
通讯作者：
Gorski, J
影响因子：
--
作者：
Hunter, CA;Tomas, S
通讯作者：
Tomas, S
DOI：
10.1016/0167-5699(92)90131-p
发表时间：
1992-02-01
期刊：
IMMUNOLOGY TODAY
影响因子：
--
作者：
SADEGHNASSERI, S;GERMAIN, RN
通讯作者：
GERMAIN, RN
影响因子：
--
作者：
KRUG, RR;HUNTER, WG;GRIEGER, RA
通讯作者：
GRIEGER, RA