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Background Lipid-protein interactions stabilize protein oligomers, shape their structure, and modulate their function. Whereas in vitro experiments already account for the functional importance of lipids by using natural lipid extracts, in silico methods lack behind by embedding proteins in single component lipid bilayers. However, to accurately complement in vitro experiments with molecular details at very high spatio-temporal resolution, molecular dynamics simulations have to be performed in natural(-like) lipid environments. Results To enable more accurate MD simulations, we have prepared four membrane models of E. coli polar lipid extract, a typical model organism, each at all-atom (CHARMM36) and coarse-grained (Martini3) representations. These models contain all main lipid headgroup types of the E. coli inner membrane, i.e., phosphatidylethanolamines, phosphatidylglycerols, and cardiolipins, symmetrically distributed between the membrane leaflets. The lipid tail (un)saturation and propanylation stereochemistry represent the bacterial lipid tail composition of E. coli grown at 37 ∘ C until 3/4 of the log growth phase. The comparison of the Simple three lipid component models to the complex 14-lipid component model Avanti over a broad range of physiologically relevant temperatures revealed that the balance of lipid tail unsaturation and propanylation in different positions and inclusion of lipid tails of various length maintain realistic values for lipid mobility, membrane area compressibility, lipid ordering, lipid volume and area, and the bilayer thickness. The only Simple model that was able to satisfactory reproduce most of the structural properties of the complex Avanti model showed worse agreement of the activation energy of basal water permeation with the here performed measurements. The Martini3 models reflect extremely well both experimental and atomistic behavior of the E. coli polar lipid extract membranes. Aquaporin-1 embedded in our native(-like) membranes causes partial lipid ordering and membrane thinning in its vicinity. Moreover, aquaporin-1 attracts and temporarily binds negatively charged lipids, mainly cardiolipins, with a distinct cardiolipin binding site in the crevice at the contact site between two monomers, most probably stabilizing the tetrameric protein assembly. Conclusions The here prepared and validated membrane models of E. coli polar lipids extract revealed that lipid tail complexity, in terms of double bond and cyclopropane location and varying lipid tail length, is key to stabilize membrane properties over a broad temperature range. In addition, they build a solid basis for manifold future simulation studies on more realistic lipid membranes bridging the gap between simulations and experiments.

Uterine fibroids, though benign in nature, are burdensome tumors of the myometrium and continue to weigh heavily on the landscape of women’s health. They affect millions and yet receive a fraction of the therapeutic innovation afforded to malignant diseases. Despite their prevalence, the molecular underpinnings of fibroid pathogenesis have long been met with a blind eye in drug development. Recent insights, however, reveal G-protein-coupled receptor 10 (GPR10) as a central driver of fibroid growth, promoting cell survival through the PI3K/Akt and MAPK/ERK signaling pathways following REST repression. In this study, we present a rigorous, computationally guided approach to design small interfering RNAs (siRNAs) that silence GPR10 expression at the transcriptomic level. Beginning with a library of 275 siRNA candidates, we undertook a layered in-silico refinement process, combining thermodynamic assessment, secondary structure modeling and off-target filtration, to distill a shortlist of ten high-confidence molecules. These were subjected to structural docking against Argonaute 2, the catalytic engine of the RNA-induced silencing complex, revealing siRNA8 and siRNA12 as lead candidates distinguished by robust binding affinity, high predicted silencing efficacy, which was greater than 93.5%, and precise conformational fit. Subsequent molecular dynamics simulations under CHARMM-GUI/CHARMM36m force field, confirmed the structural stability and sustained silencing potential of the complex. Collectively, these findings identify GPR10 as a therapeutically actionable driver in fibroid biology and lay the groundwork for precision RNAi strategies targeting non-malignant, yet clinically neglected, hormone-dependent disorders.

The self-assembly process of β-D-glucose oligomers on the surface of cellulose Iβ microfibril involves crystallization, and this process is analyzed herein, in terms of the length and flexibility of the oligomer chain, by means of molecular dynamics (MD) simulations. The characterization of this process involves the structural relaxation of the oligomer, the recognition of the cellulose I microfibril, and the formation of several hydrogen bonds (HBs). This process is monitored on the basis of the changes in non-bonded energies and the interaction with hydrophilic and hydrophobic crystal faces. The oligomer length is considered a parameter for capturing insight into the energy landscape and its stability in the bound form with the cellulose I microfibril. We notice that the oligomer–microfibril complexes are more stable by increasing the number of hydrogen bond interactions, which is consistent with a gain in electrostatic energy. Our studies highlight the interaction with hydrophilic crystal planes on the microfibril and the acceptor role of the flexible oligomers in HB formation. In addition, we study by MD simulation the interaction between a protofibril and the cellulose I microfibril in solution. In this case, the main interaction consists of the formation of hydrogen bonds between hydrophilic faces, and those HBs involve donor groups in the protofibril.