Thermodynamic and structural basis of phosphorylation-induced disorder-to-order transition in the regulatory light chain of smooth muscle myosin.
Thermodynamic and structural basis of phosphorylation-induced disorder-to-order transition in the regulatory light chain of smooth muscle myosin.
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DOI：
10.1021/ja803143g
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发表时间：
2008-09-17
影响因子：
15
通讯作者：
Thomas, David D.
中科院分区：
文献类型：
--
作者：
Espinoza-Fonseca, L. Michel;Kast, David;Thomas, David D.
我们对平滑肌肌球蛋白调节轻链（RLC）的磷酸化结构域（PD）进行了分子动力学模拟，以深入了解控制磷酸化诱导的无序到有序转变的热力学原理。模拟在明确的水在接近生理条件下进行，从一个理想的α-螺旋开始。在没有磷酸化的情况下，肽的螺旋周期性在T9−K11残基处被破坏，而磷酸化明显有利于螺旋周期性，与实验数据一致。使用MM/PBSA方法，我们计算出无序到有序转变的相对自由能为- 7.1 kcal/mol。大量的焓降低被大量的构象熵损失所补偿，尽管在磷酸化后螺旋增加很小（不超过三个残基）。磷酸化降低了K和R侧链的构象动力学，尤其是R16，与pS19形成盐桥。R16突变为A或E阻止了这种磷酸化依赖性排序。我们提出磷酸化通过与磷酸化结构域带正电的残基之间的短期和长期静电相互作用来平衡RLC无序到有序转变的焓-熵补偿。我们认为这种平衡是通过微妙的能量转换诱导无序到有序构象变化所必需的。
We have performed molecular dynamics simulations of the phosphorylation domain (PD) of the regulatory light chain (RLC) of smooth muscle myosin, to gain insight into the thermodynamic principles governing the phosphorylation-induced disorder-to-order transition. Simulations were performed in explicit water under near-physiological conditions, starting with an ideal α-helix. In the absence of phosphorylation, the helical periodicity of the peptide was disrupted at residues T9−K11, while phosphorylation significantly favored the helical periodicity, in agreement with experimental data. Using the MM/PBSA approach, we calculated a relative free energy of −7.1 kcal/mol for the disorder-to-order transition. A large enthalpic decrease was compensated by a large loss of conformational entropy, despite the small helical increase (no more than three residues) upon phosphorylation. Phosphorylation decreased the conformational dynamics of K and R side chains, especially R16, which forms a salt bridge with pS19. Mutation of R16 to A or E prevented this phosphorylation-dependent ordering. We propose that phosphorylation balances the enthalpy−entropy compensation of the disorder-to-order transition of RLC via short and long-range electrostatic interactions with positively charged residues of the phosphorylation domain. We suggest that this balance is necessary to induce a disorder-to-order conformational change through a subtle energy switching.
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影响因子：
4.4
作者：
Andricioaei, I;Karplus, M
通讯作者：
Karplus, M
影响因子：
2.9
作者：
Metcalfe, EE;Traaseth, NJ;Veglia, G
通讯作者：
Veglia, G
影响因子：
3.4
作者：
Paterlini, MG;Thomas, DD
通讯作者：
Thomas, DD
DOI：
10.1073/pnas.91.4.1490
发表时间：
1994-02-15
影响因子：
11.1
作者：
SWEENEY, HL;YANG, ZH;TRYBUS, KM
通讯作者：
TRYBUS, KM
影响因子：
15
作者：
Wang, J;Purisima, EO
通讯作者：
Purisima, EO