2 research outputs found
Water-Centered Interpretation of Intrinsic pPII Propensities of Amino Acid Residues: <i>In Vitro</i>-Driven Molecular Dynamics Study
Amino
acid residues of unfolded peptides in water sample only a
few basins in the Ramachandran plot, including prominent polyproline
II-like (pPII) conformations. Dynamics of guest residues, X, in GXG
peptides in water were recently reported to be dominated by pPII and
β-strand-like (β) conformations, resulting in an enthalpy–entropy
compensation at ∼300 K. Using molecular dynamics (MD) in explicit
solvent, we here examine pPII and β conformational ensembles
of 15 guest residues in GXG peptides, quantify local orientation of
water around their side chains through novel water orientation plots,
and study their hydration and hydrogen bonding properties. We show
that pPII and β ensembles are characterized by distinct water
orientations: pPII ensembles are associated with an increased population
of water oriented in parallel to the side chain surface whereas β
ensembles exhibit more heterogeneous water orientations. The backbone
hydration is significantly higher in pPII than in β ensembles.
Importantly, pPII to β hydration differences and the solvent
accessible surface area of C<sub>β</sub> hydrogens both correlate
with experimental pPII propensities. We propose that pPII conformations
are stabilized by a local, hydrogen-bonded clathrate-like water structure
and that residue-specific intrinsic pPII propensities reflect distinct
abilities of side chains to template this water structure
pH-Independence of Trialanine and the Effects of Termini Blocking in Short Peptides: A Combined Vibrational, NMR, UVCD, and Molecular Dynamics Study
Several lines of evidence now well
establish that unfolded peptides in general, and alanine in specific,
have an intrinsic preference for the polyproline II (pPII) conformation.
Investigation of local order in the unfolded state is, however, complicated
by experimental limitations and the inherent dynamics of the system,
which has in some cases yielded inconsistent results from different
types of experiments. One method of studying these systems is the
use of short model peptides, and specifically short alanine peptides,
known for predominantly sampling pPII structure in aqueous solution.
Recently, He et al. (J.
Am. Chem. Soc. 2012, 134, 1571−1576) proposed that
unblocked tripeptides may not be suitable models for studying conformational
propensities in unfolded peptides due to the presence of end effect,
that is, electrostatic interactions between investigated amino acid
residues and terminal charges. To determine whether changing the protonation
states of the N- and C-termini influence the conformational manifold
of the central amino acid residue in tripeptides, we have examined
the pH-dependence of unblocked trialanine and the conformational preferences
of alanine in the alanine dipeptide. To this end, we measured and
globally analyzed amide I′ band profiles and NMR J-coupling
constants. We described conformational distributions as the superposition
of two-dimensional Gaussian distributions assignable to specific subspaces
of the Ramachandran plot. Results show that the conformational ensemble
of trialanine as a whole, and the pPII content (χ<sub>pPII</sub> = 0.84) in particular, remains practically unaffected by changing
the protonation state. We found that compared to trialanine, the alanine
dipeptide has slightly lower pPII content (χ<sub>pPII</sub> =
0.74) and an ensemble more reminiscent of the unblocked Gly-Ala-Gly
model peptide. In addition, a two-state thermodynamic analysis of
the conformational sensitive ΔεÂ(T) and <sup>3</sup><i>J</i>(H<sup>N</sup>H<sup>α</sup>)Â(T) data obtained from
electronic circular dichroism and H NMR spectra indicate that the
free energy landscape of trialanine is similar in all protonation
states. MD simulations for the investigated peptides corroborate this
notion and show further that the hydration shell around unblocked
trialanine is unaffected by the protonation/deprotonation of the C-terminal
group. In contrast, the alanine dipeptide shows a reduced water density
around the central residue as well as a less ordered hydration shell,
which decreases the pPII propensity and reduces the lifetime of sampled
conformations