Adenylate Kinase (AK) is a signal transducing protein that regulates cellular energy homeostasis balancing between different conformations. An alteration of its activity can lead to severe pathologies such as heart failure, cancer and neurodegenerative diseases. A comprehensive elucidation of the large-scale conformational motions that rule the functional mechanism of this enzyme is of great value to guide rationally the development of new medications. Here using a metadynamics-based computational protocol we elucidate the thermodynamics and structural properties underlying the AK functional transitions. The free energy estimation of the conformational motions of the enzyme allows characterizing the sequence of events that regulate its action. We reveal the atomistic details of the most relevant enzyme states, identifying residues such as Arg119 and Lys13, which play a key role during the conformational transitions and represent druggable spots to design enzyme inhibitors. Our study offers tools that open new areas of investigation on large-scale motion in proteins.
In this work, a theoretical protocol based on classical molecular dynamics has been defined, in order to study weak non-covalent interactions in diphenyl disulfide based compounds. This protocol is then used to study the influence of hydrogen bonds and π-π stacking in four selected cases, namely, monosubstituted and amine ortho trisubstituted urea and urethane-based diphenyl disulfides. In all cases, it has been observed that hydrogen bonds are much more relevant than π-π stacking, which has little influence. In addition, hydrogen bonds are the responsible to maintain the polymeric chains close, so that the disulfides may reach the reacting region, even in urethane-based materials, where the lower amount of hydrogen bonds formed make the chains more flexible and mobile. Combining the results obtained by classical molecular dynamics with those obtained earlier by means of quantum mechanics, we conclude that there are two main factors that are relevant to the self-healing properties of disulfide-based materials: firstly, the capacity to generate sulfenyl radicals by breaking the disulfide S-S bond and, secondly, the ability of these radicals to attack neighboring disulfides. The former is dominated by the bond dissociation energy of the S-S bond, while the latter is strongly influenced by two other factors. On the one hand, the hydrogen bonding interactions established between chains, and on the other, the energy barriers for the attack of sulfur radicals to neighbor disulfides. We have defined three new parameters to estimate the influence of these features, with the aim of predicting the self-healing capacity of disulfides and related materials, which will help experimentalists in the development of improved materials.
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