Relationship between energy distribution and fold stability: Insights from molecular dynamics simulations of native and mutant proteins

Most proteins must fold to a well-defined structure with a minimal
stability to perform their function. Here we use a simple, molecular
dynamics-based, energy decomposition approach to map the principal
energetic interactions in a set of proteins representative of different
folds. This work involves the all-atom simulation and analysis of the
native structures and mutants of five different proteins representative
of an all-alpha (yACPB, Protein A), all-beta (SH3), and a mixed
alpha/beta fold (Proteins G and L). Given a certain structure, a native
sequence and a set Of mutants, we show that our model discriminates the
ability of a mutation to yield a more or less stable protein, in
agreement with experimental data, catching the principal energetic
determinants of protein stabilization. Our approach identifies the
interaction determinants responsible to define a fold and shows that
mutations can either modulate the strength of pair-wise coupling between
residues important for folding or modify the profile of the principal
interactions. Furthermore, we address the question of how to evaluate
the fitness of a sequence to a given structure by comparing the
information contained in the energy map, which recapitulates the
chemistry of the sequence, to that contained in the contact map, which
recapitulates the fold topology. The results show that the better fit
between the energetic properties of the sequence and the fold topology
corresponds to a higher stabilization of the protein. We discuss the
relevance of these observations to the analysis of protein designability
and to the rational evolution of new sequences.