Trinucleotide repeat expansions (CAG) lead to increase in glutamine residues and hence increase in glutamine stretch. This leads to number of neurodegenerative diseases. Therefore, the conformation of poly Q of varyin...Trinucleotide repeat expansions (CAG) lead to increase in glutamine residues and hence increase in glutamine stretch. This leads to number of neurodegenerative diseases. Therefore, the conformation of poly Q of varying chain lengths has been investigated by quantum mechanical and molecular dynamics approaches. Glutamine contains amide linkage in the side chain. It is the interaction between side chain amide linkage and the peptide bond of the backbone which dictates the conformational behaviour. Some of the glutamine residues adopt phi psi values corresponding to poly-L-proline type II structure. Not more than three glutamine residues are found to have the same set of values and hence polyglutamine is adopting random coil structure. Carbonyl-carbonyl, CH-O interactions and hydrogen bond formation involving backbone and side chain amide chain linkages are found to contribute to the stability of the adopted structure. In simulation studies due to interaction of water molecules with the amide linkages the values undergo change and this leads to weakening of carbonyl-carbonyl interactions and hydrogen bonds. The conformational behaviour of polyglutamine peptides is shown to be chain length dependent and this may provide some insight regarding the aggregation behaviour of proteins containing poly Q stretch. Possibly this is the first systematic study of the conformational behaviour of polyglutamine peptides.展开更多
Single nucleotide replacing mutations in genes cause a number of diseases, but sometimes these mutations mimic other genetic mutations such as trinucleotide repeats expansions. A mutation in codon GGG→GCG results in ...Single nucleotide replacing mutations in genes cause a number of diseases, but sometimes these mutations mimic other genetic mutations such as trinucleotide repeats expansions. A mutation in codon GGG→GCG results in Gly→Ala at the N-terminal of PABPN1 protein that mimics the trinucleotide repeat expansion disease called Oculopharyngeal muscular dystrophy (OPMD). Molecular dynamics simulations in water with peptide models having sequence Ac-A10-GA2GG-NHme (peptide A) and Ac-A10A3GG-NHme (peptide B) reveal an increase in the length of helical segment in peptide B. The α-helical length is found to be stable in peptide B with starting geometry of a right handed helix, while in the case peptide A, the helical length is short. The interactions of water molecules at terminals, side chain-backbone interactions and hydrogen bonds provide stability to resultant conformation. The adopted helix by the poly-Ala stretch may lead to masking some other active parts of the PABPN1 that may trigger the aggregation, decrease in degradation and/or impaired function of protein. Hence, further studies with N-terminal may be helpful to understand unclear disease mechanism.展开更多
文摘Trinucleotide repeat expansions (CAG) lead to increase in glutamine residues and hence increase in glutamine stretch. This leads to number of neurodegenerative diseases. Therefore, the conformation of poly Q of varying chain lengths has been investigated by quantum mechanical and molecular dynamics approaches. Glutamine contains amide linkage in the side chain. It is the interaction between side chain amide linkage and the peptide bond of the backbone which dictates the conformational behaviour. Some of the glutamine residues adopt phi psi values corresponding to poly-L-proline type II structure. Not more than three glutamine residues are found to have the same set of values and hence polyglutamine is adopting random coil structure. Carbonyl-carbonyl, CH-O interactions and hydrogen bond formation involving backbone and side chain amide chain linkages are found to contribute to the stability of the adopted structure. In simulation studies due to interaction of water molecules with the amide linkages the values undergo change and this leads to weakening of carbonyl-carbonyl interactions and hydrogen bonds. The conformational behaviour of polyglutamine peptides is shown to be chain length dependent and this may provide some insight regarding the aggregation behaviour of proteins containing poly Q stretch. Possibly this is the first systematic study of the conformational behaviour of polyglutamine peptides.
文摘Single nucleotide replacing mutations in genes cause a number of diseases, but sometimes these mutations mimic other genetic mutations such as trinucleotide repeats expansions. A mutation in codon GGG→GCG results in Gly→Ala at the N-terminal of PABPN1 protein that mimics the trinucleotide repeat expansion disease called Oculopharyngeal muscular dystrophy (OPMD). Molecular dynamics simulations in water with peptide models having sequence Ac-A10-GA2GG-NHme (peptide A) and Ac-A10A3GG-NHme (peptide B) reveal an increase in the length of helical segment in peptide B. The α-helical length is found to be stable in peptide B with starting geometry of a right handed helix, while in the case peptide A, the helical length is short. The interactions of water molecules at terminals, side chain-backbone interactions and hydrogen bonds provide stability to resultant conformation. The adopted helix by the poly-Ala stretch may lead to masking some other active parts of the PABPN1 that may trigger the aggregation, decrease in degradation and/or impaired function of protein. Hence, further studies with N-terminal may be helpful to understand unclear disease mechanism.
