Ideal gas behavior of rotamerically defined conformers in native globular proteins

Protein conformational transitions, which are essential for function, may be driven either by entropy or enthalpy when molecular systems comprising solute and solvent molecules are the focus[1, 2]. Revealing thermodynamic origin of a given molecular process is an important but difficult task, and general principles governing protein conformational distributions remain elusive. Here we demonstrate that when protein molecules are taken as thermodynamic systems and solvents being treated as the environment, conformational entropy is an excellent proxy for free energy and is sufficient to explain protein conformational distributions. Specifically, by defining each unique combination of side chain torsional state as a conformer, the population distribution (or free energy) on an arbitrarily given order parameter is approximately a linear function of conformational entropy. Additionally, span of various microscopic potential energy terms is observed to be highly correlated with both conformational entropy and free energy. Presently widely utilized free energy proxies, including minimum potential energy[3, 4, 5], average potential energy terms by themselves[6] or in combination with vibrational entropy[7], are found to correlate with free energy rather poorly. Therefore, our findings provide a fundamentally new theoretical base for development of significantly more reliable and efficient next generation computational tools, where the number of available conformers, rather than poential energy of microscopic configurations, is the central focus. We anticipate that many related research fields, including structure based drug design and discovery, protein design, docking and prediction of general intermolecular interactions involving proteins, are expected to benefit greatly.