Multiscale Modeling of Amyloid Fibrils Formed by Aggregating Peptides Derived from the Amyloidogenic Fragment of the A-Chain of Insulin.

Michał Koliński,Robert Dec,Wojciech Dzwolak

doi:10.3390/ijms222212325

Abstract

Computational prediction of molecular structures of amyloid fibrils remains an exceedingly challenging task. In this work, we propose a multi-scale modeling procedure for the structure prediction of amyloid fibrils formed by the association of ACC1-13 aggregation-prone peptides derived from the N-terminal region of insulin’s A-chain. First, a large number of protofilament models composed of five copies of interacting ACC1-13 peptides were predicted by application of CABS-dock coarse-grained (CG) docking simulations. Next, the models were reconstructed to all-atom (AA) representations and refined during molecular dynamics (MD) simulations in explicit solvent. The top-scored protofilament models, selected using symmetry criteria, were used for the assembly of long fibril structures. Finally, the amyloid fibril models resulting from the AA MD simulations were compared with atomic force microscopy (AFM) imaging experimental data. The obtained results indicate that the proposed multi-scale modeling procedure is capable of predicting protofilaments with high accuracy and may be applied for structure prediction and analysis of other amyloid fibrils.

Highlights

The often polymorphic and non-crystallizable character of amyloid fibrils hampers the widespread use of high-resolution structure-determining tools such as solid-state nuclear magnetic resonance and X-ray diffraction
The obtained protofilament models were used for the assembly of the final amyloid fibril models, which were subjected to molecular dynamics (MD) refinement within the explicit solvent environment
CABS-dock for the prediction of prediction protofilament structures assembled from short peptides, we selected three fibrils with known structures assembled from short peptides, we selected three fibrils with known experi- experimentally resolved in database

Summary

Introduction

The sheer complexity of conformational transitions leading from singly dispersed protein monomers to an amyloid architecture, with large numbers of molecules involved, and the presence of kinetic traps, pose even bigger challenges to computational studies on amyloid-formation [9–11]. Coarse-grained (CG) methods produce simplistic self-assembly models lacking realistic rendering of fine interactions between fibrils and the environment while computational costs of all-atom (AA) molecular dynamics (MD) of realistic systems (i.e., involving many aggregating protein monomers at relatively low concentration in the aqueous environment) are often prohibitive. An attractive alternative to straightforward AA MD simulations may be a multiscale approach combining fast CG simulations, with MD refinement of the resulting structures. In this way, modeling the evolution of large molecular systems becomes feasible even at prolonged timescales. A plethora of CG approaches has been described earlier, very few of them provide the necessary resolution and computational acceleration while maintaining an easy connection with more accurate methods [12]

Methods

Results

Conclusion