Taylor Cooper A, Miller Bill R, Shah Soleil S, Parish Carol A
Department of Chemistry, Gottwald Center for the Sciences, University of Richmond, Richmond, Virgina, 23173.
Department of Chemistry, Truman State University, Kirksville, Missouri, 63501.
Proteins. 2017 Feb;85(2):221-234. doi: 10.1002/prot.25208. Epub 2016 Nov 28.
Mutations in the amyloid precursor protein (APP) are responsible for the formation of amyloid-β peptides. These peptides play a role in Alzheimer's and other dementia-related diseases. The cargo binding domain of the kinesin-1 light chain motor protein (KLC1) may be responsible for transporting APP either directly or via interaction with C-jun N-terminal kinase-interacting protein 1 (JIP1). However, to date there has been no direct experimental or computational assessment of such binding at the atomistic level. We used molecular dynamics and free energy estimations to gauge the affinity for the binary complexes of KLC1, APP, and JIP1. We find that all binary complexes (KLC1:APP, KLC1:JIP1, and APP:JIP1) contain conformations with favorable binding free energies. For KLC1:APP the inclusion of approximate entropies reduces the favorability. This is likely due to the flexibility of the 42-residue APP protein. In all cases we analyze atomistic/residue driving forces for favorable interactions. Proteins 2017; 85:221-234. © 2016 Wiley Periodicals, Inc.
淀粉样前体蛋白（APP）的突变是淀粉样β肽形成的原因。这些肽在阿尔茨海默病及其他与痴呆相关的疾病中起作用。驱动蛋白-1轻链运动蛋白（KLC1）的货物结合结构域可能负责直接运输APP或通过与c-Jun氨基末端激酶相互作用蛋白1（JIP1）相互作用来运输APP。然而，迄今为止，尚未在原子水平上对这种结合进行直接的实验或计算评估。我们使用分子动力学和自由能估计来衡量KLC1、APP和JIP1二元复合物的亲和力。我们发现所有二元复合物（KLC1:APP、KLC1:JIP1和APP:JIP1）都包含具有有利结合自由能的构象。对于KLC1:APP，包含近似熵会降低其有利性。这可能是由于42个残基的APP蛋白具有灵活性。在所有情况下，我们都分析了有利相互作用的原子/残基驱动力。《蛋白质》2017年；85:221 - 234。© 2016威利期刊公司。
