Overview

Biomolecular self-assembly is governed by interactions and processes on a wide range of length- and time-scales. For simulations investigating biomolecular self-assembly approaches are required, which cover these scales and the respective levels of resolution. Multiscale simulation methods combine and systematically link in an hierarchical order multiple levels of resolution. In our group we develop multiscale methods that bridge from the atomistic (microscopic) to a coarser (mesocopic) level for the description of biomolecules. In our simulations the focus is on protein aggregation and the protein-protein interactions driving this process. Within the variety of protein aggregation processes we currently concentrate on amyloid aggregation, which plays a major role in amyloid diseases, such as Alzheimer's disease.

Topics

The Alzheimer's Aβ peptide interacting with lipid bilayers

The etiology of Alzheimer's disease is thought to be linked to interactions between the amyloid β-peptide (Aβ) and neural cell membranes. Membrane disruption and increased ion conductance have been observed in vitro in the presence of Aβ, and it is assumed that the same phenomena occur in the brain of Alzheimer's patients. The effects of Aβ on lipid behavior have been characterized experimentally, but structural and causal details are lacking. Simulations of Aβ in a bilayer environment may provide the information necessary to explain the toxicity of Aβ. We follow different simulation approaches, such as molecular dynamics and global optimization using the basin hopping algorithm to gain a better understanding of the interactions between Aβ and lipid bilayers.

D-peptides for the therapy of Alzheimer's disease

In the group of Dieter Willbold (ICS-6: Structural Biochemistry, Forschungszentrum Jülich) peptides consisting of the D-enantiomers of amino acids (D-peptides) were searched for binding to Aβ (1-42). D-peptides are thought to be protease resistant and less immunogenic than the respective L-enantiomers and can be identified by mirror image phage display. From screenings of a randomized 12mer peptide library one peptide called D3 could be identified that was shown to reduce Aβ aggregation and cytotoxicity in vitro. Furthermore, D3 improves the cognitive performance of transgenic mice who develop elevated levels of Aβ at four month of age. Therefore, D3 is a good starting point for therapy development. Using molecular simulations we aim to elucidate the binding mechanism between D3 and Aβ. This knowledge would lead to a better understanding of Alzheimer's disease in general and facilitate the improvement of therapeutic approaches based on D-peptides.

Coarse-grained simulations of amyloid aggregation

Many biologically interesting phenomena occur on a time scale that is too long to be studied by atomistic simulations. These phenomena include the dynamics of large proteins and self-assembly of biological materials, such as amyloid aggregation. Coarse-grained (CG) molecular modeling allows computer simulations to be run on length and time scales that are 2–3 orders of magnitude larger compared to atomistic simulations, providing a bridge between the atomistic and the mesoscopic scale. Currently, we are testing existing CG force fields like MARTINI for their suitability to model amyloid aggregation and developing our own CG force field.

Development of solvent models for biomolecular simulations

For the representation of the solvent in biomolecular simulations one can generally choose between the atomistic representation and an implicit description of the solvent. The former approach is too detailed for most parts of the solvent and thus computationally wasteful, while the latter neglects specific solute-solvent interactions. These shortcomings have led to the development of hybrid explicit/implicit solvation models. In our group we are currently developing such a hybrid solvation model, which can be employed in multiscale simulations.

Dimerization of the human GABAA receptor associated protein GABARAP

Gamma-aminobutyric acid type A receptor-associated protein (GABARAP) belongs to a family of small ubiquitin-like adaptor proteins implicated in intracellular vesicle trafficking and autophagy. The data from various NMR experiments suggest the presence of distinct conformational states and provide support for self-association of GABARAP molecules. We employ various molecular simulation techniques to study the dimerization of GABARAP.