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Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
147
110-POS
Board 30
Computational Studies of Co-translational Protein Folding and Misfolding on the
Ribosome
Tomasz Wlodarski
1,2
, Lisa D. Cabrita
2
, Chrisopher A. Waudby
2
, Anaïs M. Cassaignau
2
, Annika
Deckert
3
, Xiaolin Wang
4
, Abid Javed
2
, Michele Vendruscolo
1
, John Christodoulou
2
.
1
University of Cambridge, Cambridge, United Kingdom,
2
University College London, London,
United Kingdom,
3
Max Delbrück Center for Molecular Medicine, Berlin, Germany,
4
Max Planck
Institute for Biophysical Chemistry, Göttingen, Germany.
How a protein acquires its biologically active structure is a key biological question, since folding
is closely linked to a wide range of cellular processes, and where aberrant folding can result in
aggregation, a process that have been strongly implicated in several human disorders, including
Alzheimer’s and Parkinson’s diseases. Currently, there is very little understanding of the
differences between folding that occurs on the ribosome relative to that of isolated proteins, as
there are very few high-resolution structural and dynamical studies detailing the process of co-
translational folding.
In order to change this picture I have been using bioinformatics, structure-based models and all-
atom molecular dynamics simulation, where I combine enhance sampling methods
(metadynamics) with structural restraints from various NMR and CryoEM experiments to study
two model ribosomal nascent chain (RNC) systems: (a) the immunoglobulin-like domain and (b)
alpha-synuclein. First system provides understanding of the folded-unfolded transition in a single
globular domain, whereas second is offering unique insights into the capacity for an unfolded
nascent chain (the first state visited by all nascent chains) to sample conformational space, as
well as understand the role of the ribosomal surface as a protective strategy to guard against
misfolding. These models offer the unique capacity to for the first time comprehensively
characterise both structure and dynamics during co-translational protein folding in an
unprecedented level of atomistic detail.