Random Coil to Globular Thermal Response (H3.1) Figure 1. Residue-residue interaction matrix elements of MJ,2 BT,7 and BFKV.8 The matrix elements are labeled 1–210: e1,1, e1,2, …, e1,20, e2,2, e2,3, …, e2,20, …, e20,20 based on hydropathy index 1I 2V 3L 4F 5C 6M 7A 8G 9T 10S 11W 12Y 13P 14H 15Q 16 N 17D 18 E 19K 20R. doi:10.1371/journal.pone.0049352.g001 gained from the snapshots and animations during the course of simulation. For example, see a typical snapshot of the histone at a representative temperature resulting from MJ interaction in Figure 2 at the end of the simulation, i.e., at t = 107 steps. Note that the conformation of the protein undergoes numerous configurations (better seen in animations) and each of the snapshots is an instantaneous configuration. At low temperature (T = 0.010), most of the residues are organized into a compact globular conformation which opens up as the temperature is increased while maintaining some degree of local assembly. The overall size of the protein increases as the temperature increases. Which sections of the local segments coagulate while others elongate depend on the specific residues in the sequence in corresponding segments. The interactions among the residues compete with the thermal energy and this competition leads to a vast ensemble of configurations. The ensemble averaging of the local and global physical quantities provides us the trend in variation of the equilibrium structure and size of the protein as a function of the temperature. The residue map of the protein structures at representative temperatures (low to high on a relative basis) with BT and BFKV potentials are presented in figures 3 and 4 respectively. Despite the difference in range of temperature in BT and BFKV schemes, we see a general systematic conformational crossover, i.e. from a compact to an elongated conformation on raising the temperature. Thus the visual inspections of the snapshots as a result of three potentials (MJ, BT, BFKV) lead to a general feature of histone H3.1, that it opens up on raising the temperature and collapses into a compact form on lowering the temperature. This may not appear dramatic, but it is particularly noteworthy that the residues in a specific sequence in H3.1 experience a diverse range of interactions but respond collectively in such an organized fashion to bring about a systematic change in global conformation (somewhat similar to homo-polymers). However, another histone (H2AX) of comparable size exhibits non-monotonic structural response [33] where the competing and cooperative effect of interacting residue leads to a very different result. Variation of the average radius of gyration (Rg) with the temperature is presented in Figure 5 as a result of the MJ potential. Despite fluctuations in the data points, a systematic variation of Rg with temperature seems to suggest a rather smooth transition around Tc,0.013–0.015 from an extended structure at high temperature (T$0.020) to a compact morphology at the low temperature (T#0.013). The dependence of the root mean square (RMS) displacement (Rc) of the center of mass of the protein with the time steps (t) also exhibits a systematic change in the global dynamics of the protein characterized by a power-law Rc/tk. For example, it changes from a nearly standstill (frozen-in) state (kR0) at low temperatures (T#0.013) to a highly mobile protein with diffusive motion (k = 1/2) at high temperatures with a range of sub- diffusive (1/2,k,0) dynamics at the intermediate temperatures in the transition regime. PLOS ONE | www.plosone.org 3 November 2012 | Volume 7 | Issue 11 | e49352