Response of Small-Scale, Methyl Rotors to Protein-Ligand Association: A Simulation Analysis of Calmodulin-Peptide Binding
Response of Small-Scale, Methyl Rotors to Protein-Ligand Association: A Simulation Analysis of Calmodulin-Peptide Binding
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DOI：
10.1021/ja901276n
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发表时间：
2009-07-29
影响因子：
15
通讯作者：
Smith, Jeremy C.
中科院分区：
文献类型：
--
作者：
Krishnan, Marimuthu;Smith, Jeremy C.
使用分子动力学模拟研究与配体（平滑肌肌球蛋白的钙调蛋白结合域（smMLCKp））结合的蛋白质（钙调蛋白（CaM））中的甲基旋转相关的自由能垒（Delta E）、熵和运动参数的变化。在 CaM 的结合形式和未络合形式中，甲基旋转自由能势垒均遵循偏高斯分布，配体结合后不会显着改变。然而，发现了特定地点的扰动。 CaM 中大约 11% 的甲基在结合时表现出大于 0.7 kcal/mol 的 Delta E 变化。甲基的旋转熵表现出对 Delta E 的非线性依赖性。检查了运动参数（甲基旋转 NMR 有序参数和弛豫时间）与 Delta E 之间的关系。低势垒甲基旋转有序参数与理想四面体的偏差高达 20%。旋转屏障的变化与蛋白质-肽结合界面的接近度之间存在相关性。发现 Delta E 中表现出较大变化的甲基报告了蛋白质中在结合时发生结构变化的元素。
Changes in the free energy barrier (Delta E), entropy, and motional parameters associated with the rotation of methyl groups in a protein (calmodulin (CaM)) on binding a ligand (the calmodulin-binding domain of smooth-muscle myosin (smMLCKp)) are investigated using molecular dynamics simulation. In both the bound and uncomplexed forms of CaM, the methyl rotational free energy barriers follow skewed-Gaussian distributions that are not altered significantly upon ligand binding. However, site-specific perturbations are found. Around 11% of the methyl groups in CaM exhibit changes in Delta E greater than 0.7 kcal/mol on binding. The rotational entropies of the methyl groups exhibit a nonlinear dependence on Delta E The relations are examined between motional parameters (the methyl rotational NMR order parameter and the relaxation time) and Delta E Low-barrier methyl group rotational order parameters deviate from ideal tetrahedrality by up to similar to 20%. There is a correlation between rotational barrier changes and proximity to the protein-peptide binding interface. Methyl groups that exhibit large changes in Delta E are found to report on elements in the protein undergoing structural change on binding.