Helix–Coil Transition at a Glycine Following a Nascent α‑Helix: A Synergetic Guidance Mechanism for Helix Growth

A detailed
understanding of forces guiding the rapid folding of
a polypeptide from an apparently random coil state to an ordered α-helical
structure following the rate-limiting preorganization of the initial
three residue backbones into helical conformation is imperative to
comprehending and regulating protein folding and for the rational
design of biological mimetics. However, several details of this process
are still unknown. First, although the helix–coil transition
was proposed to originate at the residue level (J. Chem. Phys. 1959, 31, 526–535; J. Chem. Phys. 1961, 34, 1963–1974),
all helix-folding studies have only established it between time-averaged
bulk states of a long-lived helix and several transiently populated
random coils, along the whole helix model sequence. Second, the predominant
thermodynamic forces driving either this two-state transition or the
faster helix growth following helix nucleation are still unclear.
Third, the conformational space of the random coil state is not well-defined
unlike its corresponding α-helix. Here we investigate the restrictions
placed on the conformational space of a Gly residue backbone, as a
result of it immediately succeeding a nascent α-helical turn.
Analyses of the temperature-dependent 1D-, 2D-NMR, FT-IR, and CD spectra
and GROMACS MD simulation trajectory of a Gly residue backbone following
a model α-helical turn, which is artificially rigidified by
a covalent hydrogen bond surrogate, reveal that: (i) the α-helical
turn guides the ϕ torsion of the Gly exclusively into either
a predominantly populated entropically favored α-helical (α-ϕ)
state or a scarcely populated random coil (RC-ϕ) state; (ii)
the α-ϕ state of Gly in turn favors the stability of the
preceding α-helical turn, while the RC-ϕ state disrupts
it, revealing an entropy-driven synergetic guidance for helix growth
in the residue following helix nucleation. The applicability of a
current synergetic guidance mechanism to explain rapid helix growth
in folded and unfolded states of proteins and helical peptides is
discussed.