Random Coil to Globular Thermal Response (H3.1) Figure 4. Residue map (neighboring residues along the contour within the range of interaction) of protein at different temperatures (T = 0.0050–0.0200) with BFKV potential. doi:10.1371/journal.pone.0049352.g004 The power-law scaling of the structure factor with the wave vector, S(q) / q21/n, a consequence of the spatial distribution of residues (Rg / Nn with N being the number of residues) in the protein provides an insight into the overall morphology. The wave vector in the range of the radius of gyration leads to an effective dimension De < 1/n of protein. Results of all three potentials (MJ, BT, BFKV) are consistent with our assessment about the global structure of the protein, i.e., the globular conformation De<3 in low temperature regime and a random coil (ideal chain) De<2 at the high temperatures. Because of the unique sequence of interacting residues, the segmental morphology is heterogeneous and shows enormous variability. The cooperative and competing effect of these segments is expected to exhibit complex temperature dependence as seen with other histones [33]. It is remarkable to observe such a continuous global transformation from a random coil to a globular structure on cooling. The cooperative assembly of residues seems to propagate on larger (genetic) length scales smoothly despite a rather random but unique distribution of attractive and repulsive segments (residues) of the protein. The structural response of the histone H3.1 to temperature is very different from that of the histone H2AX, which shows non-linear (non-monotonic) thermal response [33]. It must be pointed out that the histone H3.1 plays a critical role in response to the cell’s cycle in the structural response of DNA in translation, transcription, and replication while the histone H2AX is believed to be crucial in mounting the response to repairing damaged DNA [42–48]. Therefore, the differences in thermal response of the global structures of two different histones seem appropriate for performing the distinct functions of each histone. A protein can thus undergo a continuous conformational transition. Why is such a systematic thermal response in the structure of a protein important? First, to our knowledge, it is not common in such a complex protein. Second, it provides insight into the global response with respect to local characteristics of residues with its multi-scale hierarchical structural evolution. One may question that the size of the protein H3.1 (with 136 residues) is too small to observe a possible continuous change in conformation in thermodynamic limit (i.e., a protein chain with infinite size). While one cannot rule out such a possibility, completely different thermal response [33] (non-monotonic) of dissimilar proteins (e.g., H2AX) of comparable size (e.g., 143 residues) leads us to believe that the competition between the temperature and the characteristic interactions among the residues in a specific sequence is critical. Coarse graining in modeling proteins is not unique; there can be many possibilities to develop alternate and new methods that may verify, complement or provide evidence against our findings. The variety of proteins and their characteristics is so huge (even in the histone family) that identifying their common characteristics is not feasible but highly desirable. If many proteins are found to exhibit such a thermodynamic transition, then one may be able to identify their common characteristics and special features, which may help identify universality in the non-universal world of peptides and proteins. PLOS ONE | www.plosone.org 6 November 2012 | Volume 7 | Issue 11 | e49352