Sutherland Jeffrey J, O'Brien Lee A, Lillicrap David, Weaver Donald F
Department of Chemistry, Queen's University, K7L 3N6, Kingston, Ontario, Canada.
J Mol Model. 2004 Aug;10(4):259-70. doi: 10.1007/s00894-004-0194-9. Epub 2004 Aug 3.
A homology model for the A2 domain of von Willebrand factor (VWF) is presented. A large number of target-template alignments were combined into a consensus alignment and used for constructing the model from the structures of six template proteins. Molecular dynamics simulation was used to study the structural and dynamic effects of eight mutations introduced into the model, all associated with type 2A von Willebrand disease. It was found that the group I mutations G1505R, L1540P and S1506L cause significant deviations over multiple regions of the protein, coupled to significant thermal fluctuations for G1505R and L1540P. This suggests that protein instability may be responsible for their intracellular retention. The group II mutations R1597W, E1638K and G1505E caused single loop displacements near the physiologic VWF proteolysis site between Y1605-M1606. These modest structural changes may affect interactions between VWF and the ADAMTS13 protease. The group II mutations I1628T and L1503Q caused no significant structural change in the protein, suggesting that inclusion of the protease in this model is necessary for understanding their effect. [Figure: see text]. Homology model of the von Willebrand factor A2 domain
本文提出了血管性血友病因子（VWF）A2结构域的同源模型。大量的目标-模板比对结果被整合为一个一致性比对，并用于根据六种模板蛋白的结构构建该模型。分子动力学模拟用于研究引入该模型的八个突变的结构和动力学效应，这些突变均与2A型血管性血友病相关。研究发现，I组突变G1505R、L1540P和S1506L在蛋白质的多个区域引起显著偏差，G1505R和L1540P伴有显著的热波动。这表明蛋白质不稳定性可能是它们在细胞内滞留的原因。II组突变R1597W、E1638K和G1505E在生理状态下VWF蛋白水解位点Y1605-M1606附近引起单环位移。这些适度的结构变化可能会影响VWF与ADAMTS13蛋白酶之间的相互作用。II组突变I1628T和L1503Q在蛋白质中未引起显著的结构变化，这表明在该模型中纳入蛋白酶对于理解它们的效应是必要的。[图：见正文]。血管性血友病因子A2结构域的同源模型
