García Fandiño, RebecaBernadó, PauAyuso Tejedor, SaraSancho, JavierOrozco, Modesto2020-05-122020-05-122012García-Fandiño R., Bernado, P., Ayuso-Tejedor, S., Sancho, J. y Orozco, M. (2012). Defining the Nature of Thermal Intermediate in 3 State Folding Proteins: Apoflavodoxin, a Study Case. PLoS Comput Biol, vol.8(8): e10026471553-7358http://hdl.handle.net/10347/22211The early stages of the thermal unfolding of apoflavodoxin have been determined by using atomistic multi microsecondscale molecular dynamics (MD) simulations complemented with a variety of experimental techniques. Results strongly suggest that the intermediate is reached very early in the thermal unfolding process and that it has the properties of an ‘‘activated’’ form of the native state, where thermal fluctuations in the loops break loop-loop contacts. The unrestrained loops gain then kinetic energy corrupting short secondary structure elements without corrupting the core of the protein. The MD-derived ensembles agree with experimental observables and draw a picture of the intermediate state inconsistent with a well-defined structure and characteristic of a typical partially disordered protein. Our results allow us to speculate that proteins with a well packed core connected by long loops might behave as partially disordered proteins under native conditions, or alternatively behave as three state folders. Small details in the sequence, easily tunable by evolution, can yield to one or the other type of proteinseng© García-Fandino et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedApoflavodoxinFolding Proteinsjournal article10.1371/journal.pcbi.1002647open access