posted on 2013-11-11, 00:00authored byElham Hamed, Ting Xu, Sinan Keten
We
investigate the effect of poly(ethylene glycol) (PEG) side-chain
conjugation on the conformational behavior of an α-helix using
molecular dynamics simulations in explicit solvents of varying hydrophobicity.
Our simulations illustrate an increase in peptide helicity with increasing
PEG molecular weight in the range ∼400 to 1800 Da. The data
with varying PEG contour lengths as well as constant force pulling
simulations that allow control over the end-to-end length of PEG indicate
a strong inverse correlation between peptide helicity and solvent
accessible surface area (SASA). A residue-based mapping analysis reveals
that the formation of a protecting PEG shell around peptide helix
in water is facilitated by two distinct mechanisms that depend on
the solvent environment. First, cationic residues such as lysine interact
favorably with PEG due to strong polar interactions with PEG oxygen
atoms. Additionally, we find that hydrophobic residues interact strongly
with PEG to reduce their SASA in polar solvents by polymer shielding.
Our simulations illustrate that these two mechanisms that involve
side-chain chemistry and solvent polarity govern the preferred conformation
of PEG on the helix surface and thus the stability of peptide secondary
structure. These findings elucidate the molecular mechanisms underpinning
recent experimental findings on the stability and conformational dynamics
of protein–PEG conjugates.