Phenyl-Ring Dynamics in Amyloid Fibrils and Proteins: The Microscopic-Order-Macroscopic-Disorder Perspective

摘要

We have developed the microscopic-order-macroscopic-disorder (MOMD) approach for studying internal mobility in polycrystalline proteins with ²H lineshape analysis. The motion itself is expressed by a diffusion tensor, >R, the local spatial restraints by a potential, u, and the “local geometry” by the relative orientation of the model-related and NMR-related tensors. Here, we apply MOMD to phenyl-ring dynamics in several Aβ40-amyloid-fibrils, and the villin headpiece subdomain (HP36). Because the available data are limited in extent and sensitivity, we adjust u and >R in the relevant parameter ranges, fixing the “local geometry” in accordance with standard stereo-chemistry. This yields a physically well-defined and consistent picture of phenyl-ring dynamics enabling comparison between different systems. In the temperature-range of 278–308 K, u has strength of (1.7–1.8) kT and rhombicity of (2.4–2.6) kT, and >R has components of 5.0×10² ≤ R⊥ ≤ 2.0×10³ s⁻¹ and 6.3×10⁵ ≤ R|| ≤ 2.0×10⁶ s⁻¹. At 278 K fibril hydration increases the axiality of both u and >R; HP36 hydration has a similar effect at 295 K, reducing R⊥ considerably. The D23N mutation slows down the motion of the probe; Aβ40 polymorphism affects both this motion and the related local potential. The present study identifies the impact of various factors on phenyl-ring mobility in amyloid fibrils and globular proteins; the difference between the two protein forms is considerable. The distinctive impact of hydration on phenyl-ring motion and previously-studied methyl-group motion is also examined. The ²H lineshapes considered here were analyzed previously with various multi-simple-mode (MSM) models, where several simple motional modes are combined. The MOMD and MSM interpretations differ in essence.