  Neither of the two prevalent theories, namely thermodynamic stability and
kinetic stability, provides a comprehensive understanding of protein folding.
The thermodynamic theory is misleading because it assumes that free energy is
the exclusive dominant mechanism of protein folding, and attributes the
structural transition from one characteristic state to another to energy
barriers. Conversely, the concept of kinetic stability overemphasizes dominant
mechanisms that are related to kinetic factors. This article explores the
stability condition of protein structures from the viewpoint of meso-science,
paying attention to the compromise in the competition between minimum free
energy and other dominant mechanisms. Based on our study of complex systems, we
propose that protein folding is a meso-scale, dissipative, nonlinear and
non-equilibrium process that is dominated by the compromise between free energy
and other dominant mechanisms such as environmental factors. Consequently, a
protein shows dynamic structures, featuring characteristic states that appear
alternately and dynamically, only one of which is the state with minimum free
energy. To provide evidence for this concept, we analyzed the time series of
energetic and structural changes of three simulations of protein
folding/unfolding. Our results indicate that thorough consideration of the
multiple dynamic characteristic structures generated by multiple mechanisms may
be the key to understanding protein folding.
