Computational studies of the structure, dynamics and native content of amyloid-like fibrils of ribonuclease A

@article{citeulike:1758980, abstract = {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 ?-sheet layers into dry steric zippers. Proteins 2007. {\copyright} 2007 Wiley-Liss, Inc.}, address = {Istituto di Chimica del Riconoscimento Molecolare, CNR, Via Mario Bianco, 9, 20131 Milano, Italy; Dipartimento delle Scienze Biologiche, Sezione Biostrutture, Universit\`{a} di Napoli Federico II, Via Mezzocannone 16, I-80134 Naples, Italy}, author = {Colombo, Giorgio and Meli, Massimiliano and De Simone, Alfonso }, citeulike-article-id = {1758980}, doi = {10.1002/prot.21648}, journal = {Proteins: Structure, Function, and Bioinformatics}, keywords = {dynamics, protein, structure}, number = {9999}, pages = {NA+}, posted-at = {2007-10-12 07:36:37}, priority = {2}, title = {Computational studies of the structure, dynamics and native content of amyloid-like fibrils of ribonuclease A}, url = {http://dx.doi.org/10.1002/prot.21648}, volume = {9999}, year = {2007} }

TY - JOUR ID - citeulike:1758980 L3 - citeulike-article-id:1758980 TI - Computational studies of the structure, dynamics and native content of amyloid-like fibrils of ribonuclease A JF - Proteins: Structure, Function, and Bioinformatics VL - 9999 IS - 9999 SP - NA AD - Istituto di Chimica del Riconoscimento Molecolare, CNR, Via Mario Bianco, 9, 20131 Milano, Italy; Dipartimento delle Scienze Biologiche, Sezione Biostrutture, Università di Napoli Federico II, Via Mezzocannone 16, I-80134 Naples, Italy N2 - 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 ?-sheet layers into dry steric zippers. Proteins 2007. © 2007 Wiley-Liss, Inc. KW - dynamics KW - protein KW - structure AU - Colombo, Giorgio AU - Meli, Massimiliano AU - De Simone, Alfonso PY - 2007/// UR - http://dx.doi.org/10.1002/prot.21648 ER -