Water mediated ligand functional group cooperativity: the contribution of a methyl group to binding affinity is enhanced by a COO(-) group through changes in the structure and thermodynamics of the hydration waters of ligand-thermolysin complexes.
Water mediated ligand functional group cooperativity: the contribution of a methyl group to binding affinity is enhanced by a COO(-) group through changes in the structure and thermodynamics of the hydration waters of ligand-thermolysin complexes.
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DOI：
10.1021/jm300472k
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发表时间：
2012-10-11
影响因子：
7.3
通讯作者：
Hangauert, David
中科院分区：
文献类型：
--
作者：
Nasief, Nader N.;Tan, Hongwei;Kong, Jing;Hangauert, David
配体官能团可以调节彼此对配体-蛋白质结合热力学的贡献，产生正或负的协同性。四种热溶酶磷酸氨酯抑制剂的数据表明，在羧酸配体的存在下，由Me取代H引起的结合自由能和焓的差异更有利。但是微分熵就不那么有利了。这些微分热力学参数的解剖、x射线晶体学和密度泛函理论计算表明，这些协同性是由伴随H→Me取代的复杂水化壳的热力学变化引起的。具体来说，COO−减少了从S2口袋中置换水分子的焓损失和熵优势，并导致随后获得一个焓更大、熵更小、更有利的水网络。这项研究有助于理解水在配体-蛋白结合中的重要作用。
Ligand functional groups can modulate the contributions of one another to the ligand-protein binding thermodynamics, producing either positive or negative cooperativity. Data presented for four thermolysin phosphonamidate inhibitors demonstrate that the differential binding free energy and enthalpy caused by replacement of a H with a Me group, which binds in the well-hydrated S2′ pocket, are more favorable in presence of a ligand carboxylate. The differential entropy is however less favorable. Dissection of these differential thermodynamic parameters, X-ray crystallography, and density-functional theory calculations suggest that these cooperativities are caused by variations in the thermodynamics of the complex hydration shell changes accompanying the H→Me replacement. Specifically, the COO− reduces both the enthalpic penalty and the entropic advantage of displacing water molecules from the S2′ pocket, and causes a subsequent acquisition of a more enthalpically, less entropically, favorable water network. This study contributes to understanding the important role water plays in ligand-protein binding.
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影响因子：
15
作者：
Abel, Robert;Young, Tom;Friesner, Richard A.
通讯作者：
Friesner, Richard A.
影响因子：
15
作者：
GILLI, G;BELLUCCI, F;BERTOLASI, V
通讯作者：
BERTOLASI, V
DOI：
10.1073/pnas.0404641101
发表时间：
2004-08-10
影响因子：
11.1
作者：
Fernández, A;Rogale, K;Scheraga, HA
通讯作者：
Scheraga, HA
影响因子：
2.9
作者：
FEDER, J;SCHUCK, JM
通讯作者：
SCHUCK, JM
影响因子：
2.8
作者：
Graziano, Giuseppe
通讯作者：
Graziano, Giuseppe