Structural Characterization of α-Helices of Implicitly Solvated Poly-Alanine

Abstract

The structural characteristics of alpha-helices in poly-alanine-based peptides have been investigated via molecular dynamics simulation with the goal of understanding the basic features of peptide simulations within the context of a model system, classical molecular dynamics with generalized Born (GB) solvation, and to shed insight into the formation and stabilization of alpha-helices in short peptides. The effects of peptide length, terminal charges, proline substitution, and temperature on the alpha-helical secondary structure have been studied. The simulations have shown that distinct secondary structure begins to develop in peptides with lengths approaching 10 residues while ambiguous structures occur in shorter peptides. The helical content of peptides with lengths > or =10 amino acids is observed to be nearly constant up to (Ala)(40). Interestingly, terminal charges and proline in the second position from the N-terminus alter the secondary structure locally with little effect on the overall alpha-helical content of the peptide. The free energy profile of helix formation was also investigated. A large increase in free energy accompanying the formation of helices with more than two consecutive hydrogen bonds in the (i, i + 4) pattern was observed while the free energy increases linearly with additional hydrogen bonds. Values for the change in enthalpy and entropy of helix nucleation and propagation are reported. Additionally the results obtained from the GB model are compared to explicit solvent simulations of two synthetic alanine-based peptides.

Structural insights for designed alanine‐rich helices: Comparing NMR helicity measures and conformational ensembles from molecular dynamics simulation

“…Evidence has been presented that branched non-polar sidechains owe a portion of their helix destabilization to an enthalpic effect (backbone desolvation) 64 rather than only the classical unfolding entropy expectation. The present experimental studies only confirm a helix-favoring effect of C-terminal Lys/Arg residues, which likely reflects a Coulombic interaction with the helix macrodipole 65 rather than backbone desolvation or an H-bonding interaction.…”

“…A modest increase in helicity due to placing Lys, Arg or d -Arg at the C-terminal position can be rationalized as an interaction with the helix macrodipole. 65 A resolution of the questions concerning the specific Ccapping effects of positively charged sidechains, particularly of the d -Arg function, will require studies of additional peptides with both L- and d -configured terminal groups and other polar functions. Here also, the comparison of experimental data and computational simulations should be particularly useful.…”

Tyrosine residues 654 and 670 in β-catenin are crucial in regulation of Met–β-catenin interactions

“…Although crystal structure like the ones described previously would be needed to determine this, we examined the amino acid sequence around the residues 654 and 670 [36,38]. We found a proline residue between these two residues, which has previously been shown to be responsible to turn over the helix structure [39]. Such an event would place tyrosine residues 654 and 670 more closely, for appropriate interaction.…”

Can Raman Optical Activity Separate Axial from Local Chirality? A Theoretical Study of Helical Deca‐Alanine

“…We have chosen deca-alanine as a model for helical structures in peptides and proteins since 10 residues represent the minimum length needed to stabilize such a secondary structure in proteins [16] and because alanine is the smallest chiral amino acid. The structures of both deca-alanine molecules were optimized starting from an ideal right-handed a-helix.…”