Computational investigations of protein dynamics and its implication in cellular functions: two cases on membrane sculpting by protein complexes and molecular origin of Parkinson's disease

Proteins are complex machineries dedicated to drive many functions in eukaryotic cells. In this article, two cases of protein dynamics and their implications to cellular functions are discussed with computational approaches: membrane sculpting by F-BAR domains and transient β-hairpin structure in α-synuclein. Interplay between cellular membranes and their peripheral proteins drives many processes in eukaryotic cells. Proteins of the Bin/Amphiphysin/Rvs (BAR) domain family, in particular, play a role in cellular morphogenesis, for example curving planar membranes into tubular membranes. However, it is still unclear how F-BAR domain proteins act on membranes. Electron microscopy revealed that, in vitro, F-BAR proteins form regular lattices on cylindrically deformed membrane surfaces. Using all-atom and coarse-grained (CG) molecular dynamics simulations, we show that such lattices, indeed, induce tubes of observed radii. A 250 ns all-atom simulation reveals that F-BAR domain curves membranes via the so-called “scaffolding” mechanism. Plasticity of the F-BAR domain permits conformational change in response to membrane interaction, via partial unwinding of the domain’s 3-helix bundle structure. A CG simulation covering more than 350 µs provides a dynamic picture of membrane tubulation by lattices of F-BAR domains. A series of CG simulations identified the optimal lattice type for membrane sculpting, which matches closely the lattices seen through cryo-electron microscopy. The molecular dynamics study others, thereby, both a large-scale picture of membrane sculpting by F-BAR domain lattices as well as atomic-level dynamic information about the involvement of the individual F-BAR domain and its interactions with partner F-BAR domains and membrane in the sculpting process. Parkinson’s disease is a common neurodegenerative disorder that originates from the intrinsically disordered peptide α-synuclein aggregating into fibrils. It remains unclear how α-synuclein monomers undergo conformational changes leading to aggregation and formation of fibrils characteristic for the disease. In the present study, we perform molecular dynamics simulations (over 150 μs in aggregated time) using a hybrid-resolution model, PACE, to characterize in atomic detail structural ensembles of wild type and mutant monomeric α-synuclein in aqueous solution. The simulations reproduce structural properties of α-synuclein characterized in experiments, such as secondary structure content, long-range contacts, chemical shifts and 3J(HNHCα )-coupling constants. Most notably, the simulations reveal that a short fragment encompassing region 38-53, adjacent to the non-Amyloid-β component region, exhibits a high probability of forming a β-hairpin; this fragment, when isolated from the remainder of α-synuclein, fluctuates frequently into its β-hairpin conformation. Two disease-prone mutations, namely A30P and A53T, significantly accelerate the formation of a β-hairpin in the stated fragment. We conclude that the formation of a β-hairpin in region 38-53 is a key event during α-synuclein aggregation. We predict further that the G47V mutation impedes the formation of a turn in the β-hairpin and slows down β-hairpin formation, thereby retarding α-synuclein aggregation.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biophysics & Computional Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2016

Author dc:creator

• Yu, Hang

Contributors dc:contributor

• Schulten, Klaus
• Tajkhorshid, Emad
• Grosman, Claudio
• Luthey-Schulten, Zan

• Molecular dynamics simulation
• molecular dynamics (MD) simulation
• Protein
• Membrane
• Curvature
• F-BAR domain
• Parkinson’s disease
• α-synuclein
• β-hairpin

Statement dc:rights

• Copyright 2015 Hang Yu

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/89115

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/89115