Folding and Misfolding of Designed Heteropolymer Chains with Mutations
نویسندگان
چکیده
We study the impact of mutations (changes in amino acid sequence) on the thermodynamics of simple protein-like heteropolymers consisting of N monomers, representing the amino acid sequence. The sequence is designed to fold into its native conformation on a cubic lattice. It is found that quite a large fraction, between one half and one third of the substitutions, which we call 'cold errors', make important contributions to the dynamics of the folding process, increasing folding times typically by a factor of two, the altered chain still folding into the native structure. Few mutations ('hot errors'), have quite dramatic effects, leading to protein misfolding. Our analysis reveals that mutations affect primarily the energetics of the native conformation and to a much lesser extent the ensemble of unfolded conformations, corroborating the utility of the " energy gap " concept for the analysis of folding properties of protein-like heteropolymers.
منابع مشابه
ar X iv : c on d - m at / 9 70 51 84 v 1 1 9 M ay 1 99 7 Folding and Misfolding of Designed Heteropolymer Chains with Mutations
We study the impact of mutations (changes in amino acid sequence) on the thermodynamics of simple protein-like heteropolymers consisting of N monomers, representing the amino acid sequence. The sequence is designed to fold into its native conformation on a cubic lattice. It is found that quite a large fraction, between one half and one third of the substitutions, which we call 'cold errors', ma...
متن کاملEffects of Dimethyl Sulfoxide and Mutations on the Folding of Abeta(25-35) Peptide: Molecular Dynamics Simulations
The 25-35 fragment of the amyloid β (Aβ) peptide is a naturally occurring proteolytic by-product of its larger parent molecule that retains the amyloid characteristics and toxicity of the full length parent molecule. Aggregation of this peptide occurs rapidly in aqueous solutions and thus characterization of its folding process is very difficult. In the present study, early stages of Aβ(25–35) ...
متن کاملProtein Stability, Folding and Misfolding in Human PGK1 Deficiency
Conformational diseases are often caused by mutations, altering protein folding and stability in vivo. We review here our recent work on the effects of mutations on the human phosphoglycerate kinase 1 (hPGK1), with a particular focus on thermodynamics and kinetics of protein folding and misfolding. Expression analyses and in vitro biophysical studies indicate that disease-causing mutations enha...
متن کاملMisfolding of collagen X chains harboring Schmid metaphyseal chondrodysplasia mutations results in aberrant disulfide bond formation, intracellular retention, and activation of the unfolded protein response.
Collagen X is a short chain collagen expressed specifically by the hypertrophic chondrocytes of the cartilage growth plate during endochondral bone formation. Accordingly, COL10A1 mutations disrupt growth plate function and cause Schmid metaphyseal chondrodysplasia (SMCD). SMCD mutations are almost exclusively located in the NC1 domain, which is crucial for both trimer formation and extracellul...
متن کاملMolecular Modelling and Evaluation of Hidden Information in ABCB11 Gene Mutations
Background: Cholestatic disorders are divided in the extra and intra-hepatic that created due to the severe liver diseases. ABCB11 encodes the bile salt export pump and this gene is mutated in several forms of intrahepatic cholestasis. So far, some molecular features of this gene was studies.Objective: Using a developed web server, we identified high number of rare codons in this gene, and four...
متن کامل