Molecular dynamics simulations of spontaneous fibril formation by random-coil peptides

Abstract

Assembly of normally soluble proteins into amyloid fibrils is a cause or associated symptom of numerous human disorders, including Alzheimer's and the prion diseases. We report molecularlevel simulation of spontaneous fibril formation. Systems containing 12-96 model polyalanine peptides form fibrils at temperatures greater than a critical temperature that decreases with peptide concentration and exceeds the peptide's folding temperature, consistent with experimental findings. Formation of small amorphous aggregates precedes ordered nucleus formation and subsequent rapid fibril growth through addition of ␤-sheets laterally and monomeric peptides at fibril ends. The fibril's structure is similar to that observed experimentally.amyloid ͉ protein aggregation T he pathological manifestation of the so-called amyloid diseases, including Alzheimer's, Parkinson's, and the prion diseases, is the slow coming together of specific proteins to form fibrillar plaques or tangles rich in ␤-sheet structure (1-3) within a specific organ in the body. Although progress toward understanding the molecular-level mechanisms driving protein fibrillization has been made through in vitro studies of particular proteins, concomitant atomic-resolution computer simulation studies have been impossible due to the large system sizes required and the long timescales involved. As a consequence, to date, most atomic-resolution simulation studies of spontaneous fibril formation (4-8) have been limited to consideration of small model systems containing only a few peptides, too small to model the nucleation and subsequent growth of the large ␤-sheet complexes that are observed in experiments. Recent suggestions (1, 9, 10), however, that fibrils are stabilized by forces common to all proteins, hydrophobic interactions and backbone hydrogen bonding, and not by forces particular to a specific sequence imply that: (i) progress toward understanding the etiology of the various amyloid diseases can be made by examining the fibrillization of systems containing model proteins that are less complex than the specific amyloidogenic protein, and (ii) in silico examination of fibril formation is possible using low-tointermediate-resolution protein models provided that such models faithfully capture the essential features of protein geometry, hydrophobicity, and hydrogen bonding. We have developed an intermediate-resolution protein model to meet the latter requirements.In this work, we simulate the formation of fibrils using an intermediate-resolution protein model originally introduced by Smith and Hall (11), which we now call PRIME (Protein Intermediate-Resolution Model). PRIME is simple enough to allow the simulation of multiprotein systems over relatively long timescales yet contains sufficient detail to mirror real protein dynamics when used with discontinuous molecular dynamics (DMD), a fast alternative to conventional molecular dynamics. We are able to simulate the spontaneous formation of fibrils in systems containing up to 96 16-residue alanine-based peptide...

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

“…We then investigated the kinetics of fibril formation of Ac-KA 14 K-NH 2 peptides as a function of the peptide concentration and temperature 128,105 . Constant-temperature simulations were conducted on systems containing 48 model 16-residue peptides in the canonical ensemble at a wide variety of concentrations and temperatures.…”

Sequence-Dependent Structural Stability of Self-Assembled Cylindrical Nanofibers by Peptide Amphiphiles

“…To identify an aggregate formed during the trajectory of the simulation, individual PA molecules of a cluster must form at least two interpeptide hydrogen bonds or four hydrophobic interactions with a neighboring PA molecule in the same group. 47 This criterion ensures that an aggregate is defined by at least two or more PA molecules to form enough stable interactions.…”

Protein folding: Then and now

“…Protein folding kinetics studies using DMD simulations are reviewed in [42]. Recently, DMD simulations we used in uncovering the structural mechanisms of protein aggregation [64][65][66]. Among the fundamental challenges in studying protein folding using computer simulations are the time-scales and length-scales that can be investigated.…”

“…Among the fundamental challenges in studying protein folding using computer simulations are the time-scales and length-scales that can be investigated. DMD simulations have been shown to be useful for investigating long-timescale folding dynamics of complex biological systems such as poly-alanine aggregation [66,67] and the nucleosome core particle [68].…”