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Wild type and mutants of the HET‐s(218–289) prion show different flexibility at fibrillar ends: A simulation study
Author(s) -
Friedman Ran,
Caflisch Amedeo
Publication year - 2014
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24402
Subject(s) - mutant , fibril , wild type , monomer , molecular dynamics , biophysics , chemistry , crystallography , biology , biochemistry , computational chemistry , polymer , organic chemistry , gene
The C‐terminal segment (residues 218–289) of the HET‐s protein of the filamentous fungus Podosporina anserina is a prion‐forming domain. The structural model of the HET‐s(218–289) amyloid fibril based on solid‐state nuclear magnetic resonance (NMR) restraints shows a β solenoid topology which is comprised of a β‐sheet core and interconnecting loops. For the single‐point mutants Phe286Ala and Trp287Ala, slower aggregation rates in vitro and loss of prionic infectivity have been reported recently. Here we have used molecular dynamics to compare the flexibility of the mutants and wild type. The simulations, initiated from a trimeric aggregate extracted from the NMR structural model, show structural stability on a 100‐ns time scale for wild type and mutants. Analysis of the fluctuations along the simulations reveals that the mutants are less flexible than the wild type in the C‐terminal segment at only one of the two external monomers. Analysis of interaction energy and buried accessible surface indicates that residue Phe286 in particular is stabilized in the Trp287Ala mutant. The simulation results provide an atomistic explanation of the suggestion (based on indirect experimental evidence) that flexibility at the protofibril end(s) is required for fibril elongation. Moreover, they provide further evidence that the growth of the HET‐s amyloid fibril is directional. Proteins 2014; 82:399–404. © 2013 Wiley Periodicals, Inc.