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Simulation of pH-dependent edge strand rearrangement in human -2 microglobulin

Makineni Theoretical Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

(RECEIVED August 30, 2005; FINAL REVISION August 30, 2005; ACCEPTED October 11, 2005)

Amyloid fibrils formed from unrelated proteins often share morphological similarities, suggesting common biophysicalmechanisms for amyloidogenesis. Biochemical studies of human -2 microglobulin (₂M) have shown that its transition from a water-soluble protein to insoluble aggregates can be triggered by low pH. Additionally, biophysical measurements of ₂M using NMR have identified residues of the protein that participate in the formation of amyloid fibrils. The crystal structure of monomeric human ₂M determined at pH 5.7 shows that one of its edge -strands (strand D) adopts a conformation that differs from other structures of the same protein obtained at higher pH. This alternate -strand arrangement lacks a -bulge, which may facilitate protein aggregation through intermolecular -sheet association. To explore whether the pH change may yield the observed conformational difference, molecular dynamics simulations of ₂M were performed. The effects of pH were modeled by specifying the protonation states of Asp, Glu, and His, as well as the C terminus of the main chain. The bulged conformation of strand D is preferred at medium pH (pH 5–7), whereas at low pH (pH < 4) the straight conformation is observed. Therefore, low pH may stabilize the straight conformation of edge strand D and thus increase the amyloidogenicity of ₂M.

Keywords: molecular dynamics simulation; amyloidosis; -2 microglobulin; -sheet protein; negative design; pH-dependent conformational change

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051814306.

Reprint requests to: Jeffery G. Saven, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, USA; e-mail: saven{at}sas.upenn.edu; fax: (215) 573-2112.

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