  The free-energy landscape of the alpha-helix of protein G is studied by means
of metadynamics coupled with a solute tempering algorithm. Metadynamics allows
to overcome large energy barriers, whereas solute tempering improves the
sampling with an affordable computational effort. From the sampled free-energy
surface we are able to reproduce a number of experimental observations, such as
the fact that the lowest minimum corresponds to a globular conformation
displaying some degree of beta-structure, that the helical state is metastable
and involves only 65% of the chain. The calculations also show that the system
populates consistently a pi-helix state and that the hydrophobic staple motif
is present only in the free-energy minimum associated with the helices, and
contributes to their stabilization. The use of metadynamics coupled with solute
tempering results then particularly suitable to provide the thermodynamics of a
short peptide, and its computational efficiency is promising to deal with
larger proteins.
