Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations
Open Access
- 20 November 2009
- journal article
- research article
- Published by Wiley in Protein Science
- Vol. 19 (2), 202-219
- https://doi.org/10.1002/pro.289
Abstract
Protein aggregation into insoluble fibrillar structures known as amyloid characterizes several neurodegenerative diseases, including Alzheimer's, Huntington's and Creutzfeldt‐Jakob. Transthyretin (TTR), a homotetrameric plasma protein, is known to be the causative agent of amyloid pathologies such as FAP (familial amyloid polyneuropathy), FAC (familial amyloid cardiomiopathy) and SSA (senile systemic amyloidosis). It is generally accepted that TTR tetramer dissociation and monomer partial unfolding precedes amyloid fibril formation. To explore the TTR unfolding landscape and to identify potential intermediate conformations with high tendency for amyloid formation, we have performed molecular dynamics unfolding simulations of WT‐TTR and L55P‐TTR, a highly amyloidogenic TTR variant. Our simulations in explicit water allow the identification of events that clearly discriminate the unfolding behavior of WT and L55P‐TTR. Analysis of the simulation trajectories show that (i) the L55P monomers unfold earlier and to a larger extent than the WT; (ii) the single α‐helix in the TTR monomer completely unfolds in most of the L55P simulations while remain folded in WT simulations; (iii) L55P forms, early in the simulations, aggregation‐prone conformations characterized by full displacement of strands C and D from the main β‐sandwich core of the monomer; (iv) L55P shows, late in the simulations, severe loss of the H‐bond network and consequent destabilization of the CBEF β‐sheet of the β‐sandwich; (v) WT forms aggregation‐compatible conformations only late in the simulations and upon extensive unfolding of the monomer. These results clearly show that, in comparison with WT, L55P‐TTR does present a much higher probability of forming transient conformations compatible with aggregation and amyloid formation.Keywords
This publication has 65 references indexed in Scilit:
- Scalable molecular dynamics with NAMDJournal of Computational Chemistry, 2005
- Tetramer Dissociation and Monomer Partial Unfolding Precedes Protofibril Formation in Amyloidogenic Transthyretin VariantsJournal of Biological Chemistry, 2001
- Deuterium-proton exchange on the native wild-type transthyretin tetramer identifies the stable core of the individual subunits and indicates mobility at the subunit interfaceJournal of Molecular Biology, 2000
- A comparative analysis of 23 structures of the amyloidogenic protein transthyretinJournal of Molecular Biology, 2000
- Analysis methods for comparison of multiple molecular dynamics trajectories: applications to protein unfolding pathways and denatured ensemblesJournal of Molecular Biology, 1999
- Submillisecond kinetics of protein foldingCurrent Opinion in Structural Biology, 1997
- Identification and Characterization of the Unfolding Transition State of Chymotrypsin Inhibitor 2 by Molecular Dynamics SimulationsJournal of Molecular Biology, 1996
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996
- Acid and Thermal Denaturation of Barnase Investigated by Molecular Dynamics SimulationsJournal of Molecular Biology, 1995
- Fluctuation and Cross-correlation Analysis of Protein Motions Observed in Nanosecond Molecular Dynamics SimulationsJournal of Molecular Biology, 1995