Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment

Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer's disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and 36 chains. A variety of small metastable aggregates form and dissolve until an aggregate of a critical size and conformation arises. However, the stable oligomers, which are β-sheet-rich and feature many hydrophobic contacts, are not always growth-ready. The simulations indicate instead that these supercritical oligomers spend a lengthy period in equilibrium in which considerable reorganization takes place accompanied by exchange of chains with the solution. Growth competence of the stable oligomers correlates with the alignment of the strands in the β-sheets. The larger aggregates seen in our simulations are all composed of two twisted β-sheets, packed against each other with hydrophobic side chains at the sheet–sheet interface. These β-sandwiches show similarities with the proposed steric zipper structure for PHF6 fibrils but have a mixed parallel/antiparallel β-strand organization as opposed to the parallel organization found in experiments on fibrils. Interestingly, we find that the fraction of parallel β-sheet structure increases with aggregate size. We speculate that the reorganization of the β-sheets into parallel ones is an important rate-limiting step in the formation of PHF6 fibrils

Dynamics and allosteric information pathways of unphosphorylated c-Cbl

Human c-Cbl is a RING-type ligase and plays a central role in the protein degradation cascade. To elucidate its conformational changes related to substrate binding, we performed molecular dynamics simulations of different variants/states of c-Cbl for a cumulative time of 68 μs. Our simulations demonstrate that before the substrate binds, the RING domain samples a broad set of conformational states at a biologically relevant salt concentration, including the closed, partially open, and fully open states, whereas substrate binding leads to a restricted conformational sampling. Phe378 and the C-terminal region play an essential role in stabilizing the partially open state. To visualize the allosteric signal transmission pathways from the substrate-binding site to the 40 Å apart RING domain and identify the critical residues for allostery, we have created a subgraph from the optimal and suboptimal paths. Redundant paths are seen in the SH2 domain where the substrate binds, while the major bottlenecks are found at the junction between the SH2 domain and the linker helix region as well as that between the SH2 domain and the 4H bundle. These bottlenecks separate the paths into two overall routes. The nodes/residues at the bottlenecks on the subgraph are considered allosteric hot spots. This subgraph approach provides a general tool for network visualization and determination of critical residues for allostery. The structurally and allosterically critical residues identified in our work are testable and would provide valuable insights into the emerging strategies for drug discovery, such as targeted protein degradation

Structural and pathway complexity of β-strand reorganization within aggregates of human transthyretin(105-115) peptide

Interstrand conformational rearrangements of human transthyretin peptide (TTR(105-115)) within dimeric aggregates were simulated by means of molecular dynamics (MD) with implicit solvation model for a total length of 48 μs. The conformations sampled in the MD simulations were clustered to identify free energy minima without any projections of free energy surface. A connected graph was constructed with nodes (=clusters) and edges corresponding to free energy minima and transitions between nodes, respectively. This connected graph which reflects the complexity of the free energy surface was used to extract the transition disconnectivity graph, which reflects the overall free energy barriers between pairs of free energy minima but does not contain information on transition paths. The routes of transitions between important free energy minima were obtained by further processing the original graph and the MD data. We have found that both parallel and antiparallel aggregates are populated. The parallel aggregates with different alignment patterns are separated by nonnegligible free energy barriers. Multiroutes exist in the interstrand conformational reorganization. Most visited routes do not dominant the kinetics, while less visited routes contribute a little each but they are numerous and their total contributions are actually dominant. There are various kinds of reptation motions, including those through a β-bulge, side-chain aided reptation, and flipping or rotation of a hairpin formed by one strand. © 2007 American Chemical Society

Conformations of Islet Amyloid Polypeptide Monomers in a Membrane Environment: Implications for Fibril Formation

<div><p>The amyloid fibrils formed by islet amyloid polypeptide (IAPP) are associated with type II diabetes. One of the proposed mechanisms of the toxicity of IAPP is that it causes membrane damage. The fatal mutation of S20G human IAPP was reported to lead to early onset of type II diabetes and high tendency of amyloid formation <em>in vitro</em>. Characterizing the structural features of the S20G mutant in its monomeric state is experimentally difficult because of its unusually fast aggregation rate. Computational work complements experimental studies. We performed a series of molecular dynamics simulations of the monomeric state of human variants in the membrane. Our simulations are validated by extensive comparisons with experimental data. We find that a helical disruption at His18 is common to both human variants. An L-shaped motif of S20G mutant is observed in one of the conformational families. This motif that bends at His18 resembles the overall topology of IAPP fibrils. The conformational preorganization into the fibril-like topology provides a possible explanation for the fast aggregation rate of S20G IAPP.</p> </div

Simulations of membrane-bound wild-type hIAPP_1–25 (+3).

<p>(A) Initial position and orientation of the peptide in the membrane. All of the biomolecular images in this work were generated using the Chimera <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047150#pone.0047150-Pettersen1" target="_blank">[71]</a> package. The peptide is rendered as a ribbon with its N-terminus in blue and C-terminus in orange. The water and membrane molecules are shown by the wire model. The coloring scheme for the atoms of water and membrane are: red (O atom), blue (N atom), grey (C atom), orange (P atom) and white (H atom). The scheme is used in all of the following figures. (B) Helicity. (C) H^α chemical shifts. The black line denotes the simulation result and the grey line represents the experiment data <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047150#pone.0047150-Nanga1" target="_blank">[12]</a>. (D) Simulated (black line) and experimental (gray line) H^α secondary shifts. The average values and the error bars in (B)–(D) were calculated over five trajectories.</p

Summary of the simulations.

a<p>The multiple trajectories were carried out from the same initial structure, but different initial velocities were assigned.</p

Temperature-dependent probabilistic roadmap algorithm for calculating variationally optimized conformational transition pathways

In this paper we present a method to calculate a temperature-dependent optimized conformational transition pathways. This method is based on the maximization of the flux derived from the Smoluchowski equation and is implemented with a probabilistic roadmap algorithm. We have tested the algorithm on four systems-the Müller potential, the three-hole potential, alanine dipeptide, and the folding of ß-hairpin. Comparison is made with existing algorithms designed for the calculation of protein conformational transition and folding pathways. The applications demonstrate the ability of the algorithm to isolate a temperature-dependent optimal reaction path with improved sampling and efficiency. © 2007 American Chemical Society