Critical structural fluctuations of proteins upon thermal unfolding challenge the Lindemann criterion

Abstract

Internal subnanosecond timescale motions are key for the function of proteins, and are coupled to the surrounding solvent environment. These fast fluctuations guide protein conformational changes, yet their role for protein stability, and for unfolding, remains elusive. Here, in analogy with the Lindemann criterion for the melting of solids, we demonstrate a common scaling of structural fluctuations of lysozyme protein embedded in different environments as the thermal unfolding transition is approached. By combining elastic incoherent neutron scattering and advanced molecular simulations, we show that, although different solvents modify the protein melting temperature, a unique dynamical regime is attained in proximity of thermal unfolding in all solvents that we tested. This solvation shell-independent dynamical regime arises from an equivalent sampling of the energy landscape at the respective melting temperatures. Thus, we propose that a threshold for the conformational entropy provided by structural fluctuations of proteins exists, beyond which thermal unfolding is triggered.

Thermal Adaptation of Enzymes: Impacts of Conformational Shifts on Catalytic Activation Energy and Optimum Temperature

“…Another important aspect is that conformations at different temperatures can be generated, from the ambient regime to well above melting. A systematic difference between experimental and computed absolute T m values was observed, as already reported for other systems . This is likely due to a combination of force‐field limitations, finite sampling, and to the temperature reconstruction method.…”

Atomic scale investigation of the volume phase transition in concentrated PNIPAM microgels

“…By means of neutron scattering experiments and numerical simulations, it was found that the low-temperature evolution of the mean square displacement (MSD) of the polymer atoms shows a slope change at a temperature T C 250 K, due to the onset of anharmonic motions [23]. This phenomenon in microgels is similar to the known dynamical transition observed in proteins [24,25] and appears to be strongly driven by PNIPAM-water interactions [26].…”

Configurational Entropy of Folded Proteins and Its Importance for Intrinsically Disordered Proteins

“…In order to answer that question, we consider using the Lindemann criterion developed originally for the melting of a solid crystal [ 52 ]. The Lindemann value has been adapted to the case of proteins by replacing the crystal lattice constant, , with an average nonbonded distance [ 53 , 54 ]. Katava et al provided experimental estimates of the from inelastic neutron scattering for hen egg white lysozyme (HEWL) and, assuming = 4.75 Å, found a Lindemann value at the protein melting temperature ( ) of ~0.17–0.18, driven by the mixing in of a greater proportion of unfolded state fluctuations [ 54 ].…”