Journal article
Energetics and mechanism of the normal-to-amyloidogenic isomerization of β2-microglobulin: on-the-fly string method calculations
The journal of physical chemistry. B, Vol.116(31), pp.9371-9375
09 Aug 2012
PMCID: PMC3437544
PMID: 22793795
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
Metrics
2 Record Views
Details
- Title
- Energetics and mechanism of the normal-to-amyloidogenic isomerization of β2-microglobulin: on-the-fly string method calculations
- Creators
- Spencer T Stober - Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania 19104, USACameron F Abrams
- Publication Details
- The journal of physical chemistry. B, Vol.116(31), pp.9371-9375
- Publisher
- American Chemical Society; Washington, DC
- Grant note
- 1R01GM100472 / NIGMS NIH HHS R01 GM100472 / NIGMS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Identifiers
- 991014878096404721
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Web of Science research areas
- Chemistry, Physical