Assessment of Mutational Effects on Peptide Stability through Confinement Simulations

The evaluation of free energy differences between specific states of a
system is of fundamental interest in the study of (bio)chemical systems.
Herein, we examine the use of the recently introduced confinement method
(CM) to evaluate relative free energy changes upon protein/peptide
mutations. CM is a path-independent technique that involves the
transformation of a configurational state of the system into an ideal
crystal permitting the direct computation of free energy differences. We
illustrate the method by evaluating the differential stabilities between
native and mutant sequences of a model peptide that has been extensively
characterized by experimental approaches, the GB1 hairpin. We show a
good correlation between calculated and experimental relative
stabilities and discuss other possible applications of this method in
the context of complex molecular conversions.