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Computational studies of the structure, dynamics and native content of amyloid‐like fibrils of ribonuclease A
Author(s) -
Colombo Giorgio,
Meli Massimiliano,
De Simone Alfonso
Publication year - 2008
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.21648
Subject(s) - chemistry , fibril , molecular dynamics , supramolecular chemistry , native state , globular protein , ribonuclease , biophysics , steric effects , monomer , zipper , protein aggregation , amyloid (mycology) , amyloid fibril , protein structure , crystallography , rnase p , stereochemistry , biochemistry , biology , computational chemistry , rna , amyloid β , crystal structure , medicine , inorganic chemistry , disease , organic chemistry , algorithm , pathology , computer science , gene , polymer
The characterization at atomic resolution of amyloid‐like protein aggregates is one of the fundamental problems of modern biology. In particular, the question whether native‐like domains are retained or completely refolded in the amyloid state and the identification of possible mechanisms for macromolecular ordered aggregation represent major unresolved puzzles. To address these issues, in this article we examine the stability, dynamics, and conservation of native‐like properties of several models of a previously designed amyloid‐like fibril of RNase A (Sambashivan et al. , Nature 2005; 437:266–269). Through the use of molecular dynamics (MD) simulations, we have provided molecular‐level insights into the role of different parts of the sequence on the stability of fibrils, the collective properties of supramolecular complexes, and the presence of native‐like conformations and dynamics in supramolecular aggregates. We have been able to show that within the fibrils the three‐dimensional globular domain‐swapped units preserve the conformational, dynamical, and hydration properties typical of the monomeric state, providing a rationalization for the experimentally observed catalytic activity of fibrils. The nativeness of the globular domains is not affected by the amyloidogenic stretches, which determine the molecular recognition process underlying aggregation through the formation of a stable steric zipper motif. Moreover, through the study of the hydration features of a single sheet model, we have been able to show that polyglutamine stretches of the domain‐swapped ribonuclease tend to minimize the interaction with water in favor of sidechain–sidechain interactions, shedding light on the factors leading to the supramolecular assembly of β‐sheet layers into dry steric zippers. Proteins 2008. © 2007 Wiley‐Liss, Inc.