From medicine to sport, selective androgen receptor modulators (SARMs) have represented promising applications. The ability of SARMs to selectively interact with the androgen receptor (AR) indicates that this kind of molecule can interfere with numerous physiological and pathological processes controlled by the AR regulatory mechanism. However, critical concerns in relation to safety and potential side effects of SARMs remain under discussion and investigation. SARMs, being hydrophobic/organic compounds, can be subjected to hydrophobic interactions. In this perspective, we hypothesize that SARMs interact with lipid membranes, producing significant physical and chemical changes that could be associated with several effects that SARMs represent in biological systems. In this context, the effect of SARMs on lipid membranes mediated by non-specific interactions is little explored. Here, we report significant information related to the changes that ostarine, ligandrol, andarine, and cardarine produce in the thermodynamic properties of a lipid biomembrane model. Physical changes and chemical interactions of the systems were investigated by differential scanning calorimetry (DSC), dynamic light scattering (DLS), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), and theoretical calculations implementing density functional theory (DFT). We demonstrate that ostarine, ligandrol, andarine, and cardarine can strongly interact with a lipid biomembrane model composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and accordingly, these molecules can be incorporated into the polar/hydrophobic regions of the lipid bilayer. By employing theoretical calculations, we gained insights into the possible electrostatic interactions between SARMs and phospholipid molecules, enhancing our understanding of the driving forces behind the interactions of SARMs with lipid membranes. Overall, this investigation provides relevant knowledge related to the biophysical-chemical effects that SARMs produce in biomembrane models and could be of practical reference for promising applications of SARMs in medicine and sport.

Phylogenetic studies of the pyruvate kinase family reveal two clusters: the K⁺-dependent and -independent enzymes. Thermoplasma acidophilum pyruvate kinase belongs to the latter but possesses the conserved signature of those K⁺-dependent. Recently, we found two distinct ways for these groups to catalyze. It is interesting to elucidate how the T. acidophilum enzyme achieves its active conformation. A structural model of this enzyme revealed the presence of an extra C-terminal sequence (ECTS). To understand its role, an enzyme lacking this sequence from T. acidophilum was constructed. We then compared the kinetic parameters, far-UV CD spectra, thermal stability, molecular dynamics simulations, and oligomeric states of both the wild-type and truncated enzymes. We found that the truncated enzyme is aggregated and almost inactive, with residual 20% of the total interactions, and it exhibits a soluble fraction of smaller oligomeric states than the wild-type enzyme. These findings suggest that ECTS plays a crucial role in maintaining its active tetrameric state. This sequence is the first reported in an archaeal pyruvate kinase and is also found in other archaea and bacteria. Phylogenetic analysis of ECTS in pyruvate kinases exhibits a sparse distribution that might be explained if ECTS represents an ancient domain prone to loss.

The use of repetitive units as building blocks in protein design, mimicking evolutionary duplication events, is a valuable strategy that reduces structural complexity. Such modular designs offer an opportunity to dissect how local contributions are integrated in a context‐dependent manner. sTIM11, the first validated de novo TIM barrel, and its derivatives, the DeNovoTIM collection, were designed following a four‐fold repetition strategy. Here, we examine how chimeric constructs, generated by systematically swapping hydrophilic and hydrophobic quarters from two DeNovoTIMs, modify the energetic folding landscape. In‐depth analysis of thermal unfolding transitions revealed a complex process under thermodynamic or kinetic control, as well as evidence of residual structure at high temperatures. Our findings show that swapping quarters stabilized by different types of interactions alters the thermodynamic stability of the barrel, favoring partially unfolded intermediates where stable quarters remain folded while less stable ones unfold, ultimately leading to a loss of cooperativity.