Influence of temperature on formation of perfect tau fragment fibrils using PRIME20/DMD simulations

Abstract

We investigate the fibrillization process for amyloid tau fragment peptides (VQIVYK) by applying the discontinuous molecular dynamics method to a system of 48 VQIVYK peptides modeled using a new protein model/force field, PRIME20. The aim of the article is to ascertain which factors are most important in determining whether or not a peptide system forms perfect coherent fibrillar structures. Two different directional criteria are used to determine when a hydrogen bond occurs: the original H-bond constraints and a parallel preference H-bond constraint that imparts a slight bias towards the formation of parallel versus antiparallel strands in a b-sheet. Under the original H-bond constraints, the resulting fibrillar structures contain a mixture of parallel and antiparallel pairs of strands within each b-sheet over the whole fibrillization temperature range. Under the parallel preference H-bond constraints, the b-sheets within the fibrillar structures are more likely to be parallel and indeed become perfectly parallel, consistent with X-ray crystallography, at a high temperature slightly below the fibrillization temperature. The high temperature environment encourages the formation of perfect fibril structures by providing enough time and space for peptides to rearrange during the aggregation process. There are two different kinetic mechanisms, template assembly with monomer addition at high temperature and merging/ rearrangement without monomer addition at low temperature, which lead to significant differences in the final fibrillar structure. This suggests that the diverse fibril morphologies generally observed in vitro depend more on environmental conditions than has heretofore been appreciated.

N-terminal Prion Protein Peptides (PrP(120–144)) Form Parallel In-register β-Sheets via Multiple Nucleation-dependent Pathways

“…In PRIME20, the known backbone -angles, C␣-C␣ distances and L-isomerization constraints on each amino acid are modeled by imposing pseudo-bonds between the relevant beads. A non-biased distancebased criterion is used to judge when directional hydrogen bonds are formed and broken (50). Glycine does not have a side chain bead, and proline cannot form backbone hydrogen bonds with other residues.…”

Effects of lysine residues on structural characteristics and stability of tau proteins

“…Also, Lew and coworker found that the VQIVYK and VQIINK segments mediate the possible generation of oligomeric structures [12]. Similar computational results were found by Cheon et al They revealed potential oligomeric formations of tau proteins through the replica exchange molecular dynamics (REMD) method [14]. Also, Shea group reported the formation of tau proteins with b-sheet characteristic after deleting of the 287 th lysine residue with additional residues [15].…”

“…Similarly, Shea group investigated the stability of polymorphic Ab 9-40 fibrils according to the stacking and facing directions of subunit fibrils structures based on subunit fibrils [22]. For tau proteins, Cheon et al, investigated the diverse kinds of generated tau protein and their thermodynamic stabilities through the REMD methods [14].…”

Computational Studies of Protein Aggregation: Methods and Applications

“…A similar resolution model, PRIME (and the more recent PRIME20), has been employed extensively by Hall and colleagues (17,(91)(92)(93)(94)(95)(96) to study the kinetics of fibril formation (Figure 5d ). They used discontinuous molecular dynamics (DMD), which allows for discontinuous breaks in the energy functional by computing the reflection/transmission of particles across the discontinuity.…”

“…Fibrils for this system formed by the intermediate of amorphous aggregates that, given sufficient size, spontaneously ordered into β sheets (i.e., the nucleation growth mechanism), which subsequently extended by the addition of monomers to the ends, one at a time (templated assembly). They also simulated the fibrillization of 48 tau fragment peptides (sequence VQIVYK) at varying temperatures (92). They contrasted two hydrogen bond constraints: one favoring parallel β sheets and one with no bias to parallel versus antiparallel.…”