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Protein aggregation determinants from a simplified model: Cooperative folders resist aggregation
Author(s) -
Clark Louis A.
Publication year - 2005
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.041017305
Subject(s) - cooperativity , protein folding , folding (dsp implementation) , radius of gyration , chemistry , chain (unit) , population , chemical physics , contact order , denaturation (fissile materials) , protein aggregation , native state , crystallography , biophysics , physics , polymer , biology , biochemistry , demography , organic chemistry , astronomy , sociology , electrical engineering , nuclear chemistry , engineering
Abstract Two‐chain aggregation simulations using minimalist models of proteins G, L, and mutants were used to investigate the fundamentals of protein aggregation. Mutations were selected to break up repeats of hydrophobic beads in the sequence while maintaining native topology and folding ability. Data are collected under conditions in which all chain types have similar folded populations and after equilibrating the separated chains to minimize competition between folding and aggregation. Folding cooperativity stands out as the best single‐chain determinant under these conditions and for these simple models. It can be experimentally measured by the width of the unfolding transition during thermal denaturation and loosely related to population of intermediate‐like states during folding. Additional measures of cooperativity and other properties such as radius of gyration fluctuations and patterning of hydrophobic residues are also examined. Initial contact system states with transition‐state characteristics can be identified and are more expanded than average initial contact states. Two‐chain minimalist model aggregates are considerably less structured than their native states and have minimal domain‐swapping features.