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.

Protein-protein association properties of human βB2-crystallins.

Protein-protein association events are involved in many physiological and pathological processes. Cataract disease is a pathology that manifests protein aggregation of crystallins. β-Crystallins are present in a high proportion in the eye lens.

Conformational stability of the deamidated and mutated human βB2-crystallin.

Previous studies propose that genetic mutations and post-translational modifications in protein crystallins promote protein aggregation and are considered significant risk factors for cataract formation. The βB2-crystallin (HβB2C) forms a high proportion of proteins in the human eye lens. Different congenital mutations and post-translational deamidations in βB2-crystallin have been reported and linked to cataract formation.

Elucidating the Protonation State of the γ-Secretase Catalytic Dyad.

γ-Secretase (GS) is an intramembrane aspartyl protease that participates in the sequential cleavage of C99 to generate different isoforms of the amyloid-β (Aβ) peptides that are associated with the development of Alzheimer's disease. Due to its importance in the proteolytic processing of C99 by GS, we performed pH replica exchange molecular dynamics (pH-REMD) simulations of GS in its apo and substrate-bound forms to sample the protonation states of the catalytic dyad. We found that the catalytic dyad is deprotonated at physiological pH in our apo form, but the presence of the substrate at the active site displaces its monoprotonated state toward physiological pH.

Mechanistic regulation of γ-secretase by their substrates.

γ-Secretase (GS) is a transmembrane (TM) enzyme that plays important roles in the processing of approximately 90 substrates. The amyloid precursor protein (APP) is one of these substrates, and the peptides derived from their processing are related with the development of Alzheimer's disease. However, the mechanistic process involved in the GS substrate processing and regulation remains elusive.

Computational studies of membrane pore formation induced by Pin2.

Understanding, at the molecular level, the effect of AMPs on biological membranes is of crucial importance given the increasing number of multidrug-resistant bacteria. Being part of an ancient type of innate immunity system, AMPs have emerged as a potential solution for which bacteria have not developed resistance. Traditional antibiotics specifically act on biosynthetic pathways, while AMPs may directly destabilize the lipid membrane, but it is unclear how AMPs affect the membrane's stability.

Exploring the folding process of human βB2-crystallin using multiscale molecular dynamics and the Markov state model.

Adequate knowledge of protein conformations is crucial for understanding their function and their association properties with other proteins. The cataract disease is correlated with conformational changes in key proteins called crystallins. These changes are due to mutations or post-translational modifications that may lead to protein unfolding, and thus the formation of aggregate states.

Biophysical characterization of the insertion of two potent antimicrobial peptides-Pin2 and its variant Pin2[GVG] in biological model membranes.

The aim of this study was to investigate the factors that govern the activity and selectivity of two potent antimicrobial peptides (AMPs) using lipid membrane models of bacterial, erythrocyte and fungal cells. These models were used in calcein liposome leakage experiments to explore peptide efficiency. The AMPs (Pin2 and its variant Pin2[GVG]) showed highest affinity towards the bacterial models in the nanomolar range, followed by the erythrocyte and fungal systems.

Folding profiles of antimicrobial scorpion venom-derived peptides on hydrophobic surfaces: a molecular dynamics study.

Most helical antimicrobial peptides (AMPs) are usually unfolded in aqueous solution; however they acquire their secondary structure in the presence of a hydrophobic environment such as lipid membranes. Being the biological membranes the main target of many AMPs it is necessary to understand their way of action. Pandinin 2 (Pin2) is an alpha-helical AMP isolated from the venom of the African scorpion which shows high antimicrobial activity against Gram-positive bacteria and it is less active against Gram-negative bacteria, nevertheless, it has strong hemolytic activity.

Vasoinhibin comprises a three-helix bundle and its antiangiogenic domain is located within the first 79 residues.

Vasoinhibin belongs to a family of angiogenesis inhibitors generated when the fourth α-helix (H4) of the hormone prolactin (PRL) is removed by specific proteolytic cleavage. The antiangiogenic properties are absent in uncleaved PRL, indicating that conformational changes create a new bioactive domain. However, the solution structure of vasoinhibin and the location of its bioactive domain are unknown.

Molecular dynamics simulation of the membrane binding and disruption mechanisms by antimicrobial scorpion venom-derived peptides.

Pandinin 2 (Pin2) is an alpha-helical polycationic peptide, identified and characterized from venom of the African scorpion Pandinus imperator with high antimicrobial activity against Gram-positive bacteria and less active against Gram-negative bacteria, however it has demonstrated strong hemolytic activity against sheep red blood cells. In the chemically synthesized Pin2GVG analog, the GVG motif grants it low hemolytic activity while keeping its antimicrobial activity. In this work, we performed 12 μs all-atom molecular dynamics simulation of the antimicrobial peptides (AMPs) Pin2 and Pin2GVG to explore their adsorption mechanism and the role of their constituent amino acid residues when interacting with pure POPC and pure POPG membrane bilayers.