ArticleThe journal of physical chemistry. B2012
Energetics and mechanism of the normal-to-amyloidogenic isomerization of β2-microglobulin: on-the-fly string method calculations.
Article in The journal of physical chemistry. B, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- A Companion Guide to the String Method with Swarms of Trajectories: Characterization, Performance, and Pitfalls.Journal of chemical theory and computation · 2022Article
- String Method with Swarms-of-Trajectories, Mean Drifts, Lag Time, and Committor.The journal of physical chemistry. A · 2021Article
- Exploring Configuration Space and Path Space of Biomolecules Using Enhanced Sampling Techniques-Searching for Mechanism and Kinetics of Biomolecular Functions.International journal of molecular sciences · 2018Article
- Energetics and conformational pathways of functional rotation in the multidrug transporter AcrB.eLife · 2018Article
- Principles and Overview of Sampling Methods for Modeling Macromolecular Structure and Dynamics.PLoS computational biology · 2016Review
- Extended Phase-Space Methods for Enhanced Sampling in Molecular Simulations: A Review.Frontiers in bioengineering and biotechnology · 2015Review
- A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior.PLoS computational biology · 2014Article
- Exploring the conformational transitions of biomolecular systems using a simple two-state anisotropic network model.PLoS computational biology · 2014Article
- Collective variable approaches for single molecule flexible fitting and enhanced sampling.Chemical reviews · 2014Review
- Comparison between Mean Forces and Swarms-of-Trajectories String Methods.Journal of chemical theory and computation · 2014Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
We use on-the-fly finite temperature string method in collective variables to study the transition from a normal to an amyloidogenic conformation of β2-microglobulin. We show that the protonation state of two histidine residues is of key importance and that under acidic (protonating) conditions, the transition to the amyloidgenic form is facilitated by both displacement of N-terminal residues to disrupt a hydrophobic pocket and by side-chain/side-chain electrostatic attraction, both of which facilitate a cis-trans prolyl isomerization. The free energy barriers for the normal-to-amyloidogenic isomerization are found to be 14.9 and 7.1 kcal/mol for the neutral and protonated cases, respectively, consistent with enhanced amyloidgenesis at low pH observed both in vitro and in hemodialysis-associated amyloidosis, and somewhat lower than experimentally determined barriers for bare prolyl cis-trans isomerization. We suggest specific mutagenesis experiments which could be used to further validate the mechanism observed.
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