Scrutiny of chain-length and N-terminal effects in α-helix folding: a molecular dynamics study on polyalanine peptides.
Protein folding remains an unsolved problem as main-chain, side-chain, and solvent interactions remain entangled and have been hard to resolve. Polyalanines are promising models to analyze protein folding initiation and propagation structurally as well as energetically. In the present work, the effect of chain-length and N-terminal residue stereochemistry in polyalanine peptides are investigated for their role in the nucleation of α-helical conformation. The end-protected polyalanine peptides, tetra-alanine, Ac-LAla4-NHMe (Ia) and Ac-DAla-LAla3-NHMe (Ib), hexa-alanine, Ac-LAla6-NHMe (IIa) and Ac-DAla-LAla5-NHMe (IIb), and octa-alanine, Ac-LAla8-NHMe (IIIa) and Ac-DAla-LAla7-NHMe (IIIb), are assessed as chain-length and stereochemical-structure perturbed models. The appreciable variations in the sampling of α-helical conformation, including a sampling of α-helix folds, due to the cooperative effect of chain-length and N-terminal residue stereochemistry have been noted. The electrostatics of α-helical conformation rather than the conformational entropy of the main-chain appear to be decisive in the initiation of α-helix folding. The results of the present work will enhance our understanding on the nucleation of α-helical conformation in short peptides and aid in the design of novel peptides with α-helical structure that can modulate disease-related protein-protein interactions.
a Department of Chemistry , Indian Institute of Technology Bombay , Mumbai 400076 , India.|b Department of Chemistry, School of Basic and Applied Sciences , Sri Guru Granth Sahib World University , Fatehgarh Sahib 140406 , Punjab , India.
Bhupesh
B
Goyal
a Department of Chemistry , Indian Institute of Technology Bombay , Mumbai 400076 , India.|c Department of Chemistry , University of Toronto , Toronto , ON M5S 3H6 , Canada.
Anil
A
Kumar
a Department of Chemistry , Indian Institute of Technology Bombay , Mumbai 400076 , India.|d Department of Physics and Astronomy , Michigan State University , East Lansing , MI 48824 , USA.
Kinshuk Raj
KR
Srivastava
a Department of Chemistry , Indian Institute of Technology Bombay , Mumbai 400076 , India.
Susheel
S
Durani
D000595:Amino Acid Sequence / Q000235:genetics; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D000072756:Protein Conformation, alpha-Helical; D017510:Protein Folding; D012997:Solvents / Q000737:chemistry; D055672:Static Electricity; D013816:Thermodynamics
D010455:Peptides; D012997:Solvents; C019529:polyalanine
electrostatics of peptides; molecular dynamics simulations; polyalanine; protein folding; protein stereochemistry