Conformational Changes and Unfolding of β-Amyloid Substrates in the Active Site of γ-Secretase.

Alzheimer's disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-β (Aβ) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes a sequence of cleavages, referred as trimming, performed by γ-secretase. Here, we investigated conformational changes in a series of β-amyloid substrates (from less and more amyloidogenic pathways) in the active site of presenilin-1, the catalytic subunit of γ-secretase.

GS-SMD server for steered molecular dynamics of peptide substrates in the active site of the γ-secretase complex.

Despite recent advances in research, the mechanism of Alzheimer's disease is not fully understood yet. Understanding the process of cleavage and then trimming of peptide substrates, can help selectively block γ-secretase (GS) to stop overproduction of the amyloidogenic products. Our GS-SMD server (https://gs-smd.

Specificities of Protein Homology Modeling for Allosteric Drug Design.

The allosteric binding sites are usually located in the flexible areas of proteins, which are hardly visible in the crystal structures. However, there are notable exceptions like allosteric sites in receptors in class B and C of GPCRs, which are located within a well-defined bundle of transmembrane helices. Class B and C evolved from class A and even after swapping of orthosteric and allosteric sites the central binding site persisted and it can be used for easy design of allosteric drugs.

The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex.

Alzheimer's disease is the most common progressive neurodegenerative disorder and is characterized by the presence of amyloid β (Aβ) plaques in the brain. The γ-secretase complex, which produces Aβ, is an intramembrane-cleaving protease consisting of four membrane proteins. In this paper we investigated the amyloidogenic fragments of amyloid precursor protein (substrates Aβ and Aβ, leading to less amyloidogenic Aβ and more amyloidogenic Aβ, respectively) docked to the binding site of presenilin, the catalytic subunit of γ-secretase.

GPCRsignal: webserver for analysis of the interface between G-protein-coupled receptors and their effector proteins by dynamics and mutations.

GPCRsignal (https://gpcrsignal.biomodellab.eu/) is a webserver devoted to signaling complexes of G-protein-coupled receptors (GPCRs).

Allosteric Modulation of the CB1 Cannabinoid Receptor by Cannabidiol-A Molecular Modeling Study of the N-Terminal Domain and the Allosteric-Orthosteric Coupling.

The CB cannabinoid receptor (CBR) contains one of the longest N termini among class A G protein-coupled receptors. Mutagenesis studies suggest that the allosteric binding site of cannabidiol (CBD) involves residues from the N terminal domain. In order to study the allosteric binding of CBD to CBR we modeled the whole N-terminus of this receptor using the replica exchange molecular dynamics with solute tempering (REST2) approach.

The Hydrophobic Ligands Entry and Exit from the GPCR Binding Site-SMD and SuMD Simulations.

Most G protein-coupled receptors that bind the hydrophobic ligands (lipid receptors and steroid receptors) belong to the most populated class A (rhodopsin-like) of these receptors. Typical examples of lipid receptors are: rhodopsin, cannabinoid (CB), sphingosine-1-phosphate (S1P) and lysophosphatidic (LPA) receptors. The hydrophobic ligands access the receptor binding site from the lipid bilayer not only because of their low solubility in water but also because of a large N-terminal domain plug preventing access to the orthosteric binding site from the extracellular milieu.

GPCRM: a homology modeling web service with triple membrane-fitted quality assessment of GPCR models.

Due to the involvement of G protein-coupled receptors (GPCRs) in most of the physiological and pathological processes in humans they have been attracting a lot of attention from pharmaceutical industry as well as from scientific community. Therefore, the need for new, high quality structures of GPCRs is enormous. The updated homology modeling service GPCRM (http://gpcrm.

Aquaporin-graphene interface: relevance to point-of-care device for renal cell carcinoma and desalination.

The aquaporin superfamily of hydrophobic integral membrane proteins constitutes water channels essential to the movement of water across the cell membrane, maintaining homeostatic equilibrium. During the passage of water between the extracellular and intracellular sides of the cell, aquaporins act as ultra-sensitive filters. Owing to their hydrophobic nature, aquaporins self-assemble in phospholipids.

Approaches for Differentiation and Interconverting GPCR Agonists and Antagonists.

Predicting the functional preferences of the ligands was always a highly demanding task, much harder that predicting whether a ligand can bind to the receptor. This is because of significant similarities of agonists, antagonists and inverse agonists which are binding usually in the same binding site of the receptor and only small structural changes can push receptor toward a particular activation state. For G protein-coupled receptors, due to a large progress in crystallization techniques and also in receptor thermal stabilization, it was possible to obtain a large number of high-quality structures of complexes of these receptors with agonists and non-agonists.

Crystal structures of nematode (parasitic T. spiralis and free living C. elegans), compared to mammalian, thymidylate synthases (TS). Molecular docking and molecular dynamics simulations in search for nematode-specific inhibitors of TS.

Three crystal structures are presented of nematode thymidylate synthases (TS), including Caenorhabditis elegans (Ce) enzyme without ligands and its ternary complex with dUMP and Raltitrexed, and binary complex of Trichinella spiralis (Ts) enzyme with dUMP. In search of differences potentially relevant for the development of species-specific inhibitors of the nematode enzyme, a comparison was made of the present Ce and Ts enzyme structures, as well as binary complex of Ce enzyme with dUMP, with the corresponding mammalian (human, mouse and rat) enzyme crystal structures. To complement the comparison, tCONCOORD computations were performed to evaluate dynamic behaviors of mammalian and nematode TS structures.

Hydrophobic Ligand Entry and Exit Pathways of the CB1 Cannabinoid Receptor.

It has been reported that some hydrophobic ligands of G-protein-coupled receptors access the receptor's binding site from the membrane rather than from bulk water. In order to identify the most probable ligand entrance pathway into the CB1 receptor, we performed several steered molecular dynamics (SMD) simulations of two CB1 agonists, THC and anandamide, pulling them from the receptor's binding site with constant velocity. The four main directions of ligand pulling were probed: between helices TM4 and TM5, between TM5 and TM6, between TM7 and TM1/TM2, and toward the bulk water.

Synthesis of alpha-trifluoromethyl-beta-lactams and esters of beta-amino acids via 1,3-dipolar cycloaddition of nitrones to fluoroalkenes.

Nitrones derived from aromatic or aliphatic aldehydes or ketones react with hexafluoropropene (HFP) or 2H-pentafluoropropene (PFP) to give the respective fluorinated isoxazolidine derivatives in good yields with complete regioselectivity and moderate diastereoselectivity. Catalytic hydrogenolysis of the N-O bond under ambient pressure and temperature leads to fluorides of beta-amino acids that undergo cyclization to alpha-trifluoromethylated beta-lactams or, under acidic conditions, form esters of alpha-trifluoromethylated beta-amino acids.