Identification and structural characterization of CB1 receptor antagonists: A comprehensive virtual screening and molecular dynamics study of arachidin-2.

The cannabinoid receptor 1 (CB1) is an essential component of the endocannabinoid system, responsible for regulating various physiological processes such as pain, mood, and appetite. Despite increasing interest in the therapeutic potential of CB1 modulators, the precise mechanisms by which small molecules modulate receptor activity-particularly without fully transitioning between active and inactive states-remain partially understood. In this study, the complexity of CB1-ligand interactions was evaluated for the inactive CB1 state.

Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FF-ATP synthase.

In addition to playing a central role in the mitochondria as the main producer of ATP, FF-ATP synthase performs diverse key regulatory functions in the cell membrane. Its malfunction has been linked to a growing number of human diseases, including hypertension, atherosclerosis, cancer, and some neurodegenerative, autoimmune, and aging diseases. Furthermore, inhibition of this enzyme jeopardizes the survival of several bacterial pathogens of public health concern.

Specific inter-domain interactions stabilize a compact HIV-1 Gag conformation.

HIV-1 Gag is a large multidomain poly-protein with flexible unstructured linkers connecting its globular subdomains. It is compact when in solution but assumes an extended conformation when assembled within the immature HIV-1 virion. Here, we use molecular dynamics (MD) simulations to quantitatively characterize the intra-domain interactions of HIV-1 Gag.

Microenvironmentally controlled secondary structure motifs of apolipoprotein A-I derived peptides.

The structure of apolipoprotein A-I (apoA-I), the major protein of HDL, has been extensively studied in past years. Nevertheless, its corresponding three-dimensional structure has been difficult to obtain due to the frequent conformational changes observed depending on the microenvironment. Although the function of each helical segment of this protein remains unclear, it has been observed that the apoA-I amino (N) and carboxy-end (C) domains are directly involved in receptor-recognition, processes that determine the diameter for HDL particles.

Key structural arrangements at the C-terminus domain of CETP suggest a potential mechanism for lipid-transfer activity.

The cholesteryl-ester transfer protein (CETP) promotes cholesteryl-ester and triglyceride transfer between lipoproteins. We evaluated the secondary structure stability of a series of small peptides derived from the C-terminus of CETP in a wide range of pH's and lipid mixtures, and studied their capability to carry out disorder-to-order secondary structure transitions dependent of lipids. We report that while a mixture of phosphatidylcholine/cholesteryl-esters forms large aggregated particles, the inclusion of a series of CETP carboxy-terminal peptides in a stable α-helix conformation, allows the formation of small homogeneous micelle-like structures.

Disorder-to-order conformational transitions in protein structure and its relationship to disease.

Function in proteins largely depends on the acquisition of specific structures through folding at physiological time scales. Under both equilibrium and non-equilibrium states, proteins develop partially structured molecules that being intermediates in the process, usually resemble the structure of the fully folded protein. These intermediates, known as molten globules, present the faculty of adopting a large variety of conformations mainly supported by changes in their side chains.

Lipid dependant disorder-to-order conformational transitions in apolipoprotein CI derived peptides.

In contrast to the notion established for many years that protein function depends on rigid 3D structures, nowadays there is important evidence suggesting that non-structured segments of proteins play important roles in protein function. Therefore, disorder-to-order dynamic conformational transitions have been proposed as an attractive mechanism involved in protein-protein recognition. Our laboratory using Langmuir monolayers of apolipoproteins has previously shown that upon lateral compression at the air/water and phospholipid/water interfaces, there is an important movement of the C-terminal segment of apolipoprotein CI towards the air, considered the hydrophobic region of the monolayer and the acyl-chain region of the interface when phospholipids are used.