  The high computational cost of carrying out molecular dynamics simulations of
even small-size proteins is a major obstacle in the study, at atomic detail and
in explicit solvent, of the physical mechanism which is at the basis of the
folding of proteins. Making use of a biasing algorithm, based on the principle
of the ratchet-and-pawl, we have been able to calculate eight folding
trajectories (to an RMSD between 1.2A and 2.5A) of the B1 domain of protein G
in explicit solvent without the need of high-performance computing. The
simulations show that in the denatured state there is a complex network of
cause-effect relationships among contacts, which results in a rather
hierarchical folding mechanism. The network displays few local and nonlocal
native contacts which are cause of most of the others, in agreement with the
NOE signals obtained in mildly-denatured conditions. Also nonnative contacts
play an active role in the folding kinetics. The set of conformations
corresponding to the transition state display phi-values with a correlation
coefficient of 0.69 with the experimental ones. They are structurally quite
homogeneous and topologically native-like, although some of the side chains and
most of the hydrogen bonds are not in place.
