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- Quantum vibrational excitations and protein folding in vivoPublication . Cruzeiro, LeonorOne main hypothesis is that when triggers like water molecules or ions or other ligands, or chemical reactions, act on a protein, the energy input to the protein is in the form of local quantum vibrational excited states (the VES hypothesis).
- Knowns and unknowns in the Davydov model for energy transfer in proteinsPublication . Cruzeiro, LeonorThe Davydov model for amide I propagation in hydrogen-bonded chains of proteins is revisited. The many similarities between the mixed quantum-classical dynamical equations and those that are derived from the full quantum Davydov model while applying the so-called D-2 ansatz are highlighted. The transition from a minimum energy localized amide I state to a fully delocalized state is shown to operate in four phases, one of which is abrupt and the last of which is a fast but smooth change from a very broad yet localized state to a completely delocalized one. Exploration of the dynamical phase space at zero temperature includes the well-known soliton propagation as well as double and triple discrete breathers, and dispersion of initially localized states. The uncertainties related to the question of the thermal stability of the Davydov soliton are illustrated. A solution to the seemingly endless problem of the short radiative lifetime of the amide I excitations is proposed.
- The VES KM: a pathway for protein folding in vivoPublication . Cruzeiro, LeonorWhile according to the thermodynamic hypothesis, protein folding reproducibility is ensured by the assumption that the native state corresponds to the minimum of the free energy in normal cellular conditions, here, the VES kinetic mechanism for folding in vivo is described according to which the nascent chain of all proteins is helical and the first and structure defining step in the folding pathway is the bending of that initial helix around a particular amino acid site. Molecular dynamics simulations are presented which indicate both the viability of this mechanism for folding and its limitations in the presence of a Markovian thermal bath. An analysis of a set of protein structures formed only of helices and loops suggests that bending sites are correlated with regions bounded, on the N-side, by positively charged amino acids like Lysine and Histidine and on the C-side by negatively charged amino acids like Aspartic acid.
- Statistical evidence for a helical nascent chainPublication . Cruzeiro, Leonor; Gill, Andrew C.; Eilbeck, J. ChrisWe investigate the hypothesis that protein folding is a kinetic, non-equilibrium process, in which the structure of the nascent chain is crucial. We compare actual amino acid frequencies in loops, alpha-helices and beta-sheets with the frequencies that would arise in the absence of any amino acid bias for those secondary structures. The novel analysis suggests that while specific amino acids exist to drive the formation of loops and sheets, none stand out as drivers for alpha-helices. This favours the idea that the alpha-helix is the initial structure of most proteins before the folding process begins.
- Protein folding in vivo is a non-equilibrium processPublication . Cruzeiro, LeonorProtein refolding experiments have led to the thermodynamics hypothesis according to which the native structures of proteins are uniquely defined by their primary sequences.
- Exploring the Levinthal limit in protein foldingPublication . Cruzeiro, Leonor; Degreve, LeoAccording to the thermodynamic hypothesis, the native state of proteins is uniquely defined by their amino acid sequence. On the other hand, according to Levinthal, the native state is just a local minimum of the free energy and a given amino acid sequence, in the same thermodynamic conditions, can assume many, very different structures that are as thermodynamically stable as the native state. This is the Levinthal limit explored in this work. Using computer simulations, we compare the interactions that stabilize the native state of four different proteins with those that stabilize three non-native states of each protein and find that the nature of the interactions is very similar for all such 16 conformers. Furthermore, an enhancement of the degree of fluctuation of the non-native conformers can be explained by an insufficient relaxation to their local free energy minimum. These results favor Levinthal's hypothesis that protein folding is a kinetic non-equilibrium process.