Amyloid fibril deposits of the intrinsically disordered hIAPP peptide are found in 95% of type II diabetes patients, and the aggregation of this peptide is suggested to induce apoptotic cell-death in insulin-producing β-cells. Understanding the structure and dynamics of the hIAPP monomer in solution is thus important for understanding the nucleation of aggregation and the formation of oligomers. In this study, we identify the metastable conformational states of the hIAPP monomer and the dynamics of transitioning between them using Markov state models constructed from extensive molecular dynamics simulations. We show that the overall structure of the hIAPP peptide is random coil-like and lacks a dominant folded structure. Despite this fact, our model reveals a large number of reasonably well-populated metastable conformational states (or local free energy minima) having populations of a few percent or less. The time scales for transitioning between these states range from several microseconds to milliseconds. In contrast to folded proteins, there is no kinetic hub. More strikingly, a few states contain significant amounts of β-hairpin secondary structure and extended hydrophobic surfaces that are exposed to the solvent. We propose that these states may facilitate the nucleation of hIAPP aggregation through a significant component of the conformational selection mechanism, because they may increase their populations upon aggregation by promoting hydrophobic interactions and at the same time provide a flat geometry to seed the ordered β-strand packing of the fibrils.
Liquid–liquid phase separation (LLPS) is involved in both physiological and pathological processes. The intrinsically disordered protein Tau and its K18 construct can undergo LLPS in a distinct temperature-dependent manner, and the LLPS of Tau protein can initiate Tau aggregation. However, the underlying mechanism driving Tau LLPS remains largely elusive. To understand the temperature-dependent LLPS behavior of Tau at the monomeric level, we explored the conformational ensemble of Tau at different temperatures by performing all-atom replica-exchange molecular dynamic simulation on K18 monomer with an accumulated simulation time of 26.4 μs. Our simulation demonstrates that the compactness, β-structure propensity, and intramolecular interaction of K18 monomer exhibit nonlinear temperature-dependent behavior. 295DNIKHV300/326GNIHHK331/337VEVKSE342 make significant contributions to the temperature dependence of the β propensity of K18 monomer, while the two fibril-nucleating cores display relatively high β propensity at all temperatures. At a specific temperature, K18 monomer adopts the most collapsed state with exposed sites for both persistent and transient interactions. Given that more collapsed polypeptide chains were reported to be more prone to phase separate, our results suggest that K18 monomer inherently possesses conformational characteristics favoring LLPS. Our simulation predicts the importance of 295DNIKHV300/326GNIHHK331/337VEVKSE342 to the temperature-dependent conformational properties of K18, which is corroborated by CD spectra, turbidity assays, and DIC microscopy. Taken together, we offer a computational and experimental approach to comprehend the structural basis for LLPS by amyloidal building blocks.
In this work, we study the effects of non-Condon vibronic coupling on the quantum coherence of excitation energy transfer, via the exact dissipaton-equation-of-motion evaluations on excitonic model systems. Field-triggered excitation energy transfer dynamics and two dimensional coherent spectroscopy are simulated for both Condon and non-Condon vibronic couplings. Our results clearly demonstrate that the non-Condon vibronic coupling intensifies the dynamical electronic-vibrational energy transfer and enhances the total system-and-bath quantum coherence. Moreover, the hybrid bath dynamics for non-Condon effects enriches the theoretical calculation, and further sheds light on the interpretation of the experimental nonlinear spectroscopy.
Self-assembly processes play a key role in the fabrication of functional nano-structures with widespread application in drug delivery and micro-reactors. In addition to the thermodynamics, the kinetics of the self-assembled nano-structures also play an important role in determining the formed structures. However, as the self-assembly process is often highly heterogeneous, systematic elucidation of the dominant kinetic pathways of self-assembly is challenging. Here, based on mass flow, we developed a new method for the construction of kinetic network models and applied it to identify the dominant kinetic pathways for the self-assembly of star-like block copolymers. We found that the dominant pathways are controlled by two competing kinetic parameters: the encounter time Te, characterizing the frequency of collision and the transition time Tt for the aggregate morphology change from rod to sphere. Interestingly, two distinct self-assembly mechanisms, diffusion of an individual copolymer into the aggregate core and membrane closure, both appear at different stages (with different values of Tt) of a single self-assembly process. In particular, the diffusion mechanism dominates the middle-sized semi-vesicle formation stage (with large Tt), while the membrane closure mechanism dominates the large-sized vesicle formation stage (with small Tt). Through the rational design of the hydrophibicity of the copolymer, we successfully tuned the transition time Tt and altered the dominant self-assembly pathways.
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