  Free energy calculation is critical in predictive tasks such as protein
folding, docking and design. However, rigorous calculation of free energy
change is prohibitively expensive in these practical applications. The minimum
potential energy is therefore widely utilized to approximate free energy. In
this study, based on analysis of extensive molecular dynamics (MD) simulation
trajectories of a few native globular proteins, we found that change of minimum
and corresponding maximum potential energy terms exhibit similar level of
correlation with change of free energy. More importantly, we demonstrated that
change of span (maximum - minimum) of potential energy terms, which engender
negligible additional computational cost, exhibit considerably stronger
correlations with change of free energy than the corresponding change of
minimum and maximum potential energy terms. Therefore, potential energy span
may serve as an alternative efficient approximate free energy proxy.
