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Volume 11
Journal of Proteomics & Bioinformatics
ISSN: 0974-276X
Structural Biology 2018
September 24-26, 2018
September 24-26, 2018 | Berlin, Germany
14
th
International Conference on
Structural Biology
Modelling protein-protein interactions to elucidate molecular mechanism responsible for Ataxin-1
self-aggregation
Gianvito Grasso
IDSIA, Switzerland
T
he worldwide significant increase in the life expectancy has recently drawn the attention of the scientific community
to neurodegenerative pathologies of the elderly population. These neurodegenerative disorders arise from the abnormal
protein aggregation in the nervous tissue leading to intracellular inclusions or extracellular aggregates in specific brain areas.
Although the substantial research effort in this field, the fundamental mechanisms of protein misfolding remain somewhat
unrevealed. The multiscale nature of the protein aggregation pathway requires investigation at multiple time and length
scales to provide a deep understanding of molecular reasons responsible for the disease onset and severity. In this context,
computational molecular modelling has often demonstrated to be a powerful tool in connecting macroscopic experimental
findings to nanoscale molecular event. The present work aims at investigating molecular features of protein folding and protein-
protein interactions leading to protein aggregation in case of atax in-1 (ATX1), the protein responsible for spinocerebellar
ataxia type-1. Despite poly glutamine expansion is an essential step in the disease onset, it is now established the leading role
of AXH domain of ATX1, so far the only structured globular region identified along the protein sequence, in modulating
the aggregation pathway. However, the AXH self-association mechanism is not yet clarified and several crucial questions
remain open. The present work employs enhanced sampling techniques to fully characterize the AXH aggregation pathway
from monomer to tetramer, identifying several protein mutations responsible for the destabilization of the monomer/dimer/
tetramer equilibrium. To address this goal, classical molecular dynamics together with enhanced sampling techniques have
been employed to provide novel insights into the previously mentioned issues. Outcome of the present research represents the
basis for a future design of aggregation inhibitors that will require several key conformations identified in the present study as
molecular targets for ligand binding.
J Proteomics Bioinform 2018, Volume 11
DOI: 10.4172/0974-276X-C2-116