Ligand-induced perturbation of the HIF-2α:ARNT dimer dynamics.

Hypoxia inducible factors (HIFs) are transcription factors belonging to the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) protein family with a role in sensing oxygen levels in the cell. Under hypoxia, the HIF-α degradation pathway is blocked and dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT) makes HIF-α transcriptionally active. Due to the common hypoxic environment of tumors, inhibition of this mechanism by destabilization of HIF-α:ARNT dimerization has been proposed as a promising therapeutic strategy.

Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms.

Molecular modeling has given important contributions to elucidation of the main stages in the AhR signal transduction pathway. Despite the lack of experimentally determined structures of the AhR functional domains, information derived from homologous systems has been exploited for modeling their structure and interactions. Homology models of the AhR PASB domain have provided information on the binding cavity and contributed to elucidate species-specific differences in ligand binding.

Structural modeling of the AhR:ARNT complex in the bHLH-PASA-PASB region elucidates the key determinants of dimerization.

Elucidation of the dimerization process of the aryl hydrocarbon receptor (AhR) with the AhR nuclear translocator (ARNT) is crucial for understanding the mechanisms underlying the functional activity of AhR, including mediation of the toxicity of environmental contaminants. In this work, for the first time a structural model of the AhR:ARNT dimer encompassing the entire bHLH-PASA-PASB domain region is proposed. It is developed by using a template-based modeling approach, relying on the recently available crystallographic structures of two dimers of homologous systems in the bHLH-PAS family of proteins: the CLOCK:BMAL1 and the HIF2α:ARNT heterodimers.

Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation.

The Aryl hydrocarbon Receptor (AhR) is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT) protein, occurring through the Helix-Loop-Helix (HLH) and PER-ARNT-SIM (PAS) domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation.

Prediction of Antigenic B and T Cell Epitopes via Energy Decomposition Analysis: Description of the Web-Based Prediction Tool BEPPE.

Unraveling the molecular basis of immune recognition still represents a challenging task for current biological sciences, both in terms of theoretical knowledge and practical implications. Here, we describe the physical-chemistry methods and computational protocols for the prediction of antibody-binding epitopes and MHC-II loaded epitopes, starting from the atomic coordinates of antigenic proteins (PDB file). These concepts are the base of the Web tool BEPPE (Binding Epitope Prediction from Protein Energetics), a free service that returns a list of putative epitope sequences and related blast searches against the Uniprot human complete proteome.

Energetic and dynamic aspects of the affinity maturation process: characterizing improved variants from the bevacizumab antibody with molecular simulations.

Antibody affinity maturation is one of the fundamental processes of immune defense against invading pathogens. From the biological point of view, the clonal selection hypothesis represents the most accepted mechanism to explain how mutations increasing the affinity for target antigens are introduced and selected in antibody molecules. However, understanding at the molecular level how protein modifications, such as point mutation, can modify and modulate the affinity of an antibody for its antigen is still a major open issue in molecular biology.

Investigating allostery in molecular recognition: insights from a computational study of multiple antibody-antigen complexes.

Antibody-antigen recognition plays a key role in the immune response against pathogens. Here, we have investigated various aspects of this problem by analyzing a large and diverse set of antibodies and their respective complexes with protein antigens through atomistic simulations. Common features of antibody response to the presence of antigens are elucidated by the analysis of the proteins' internal dynamics and coordination in different ligand states, combined with the analysis of the interaction networks implicated in the stabilization of functional structures.

Blood microRNA changes in depressed patients during antidepressant treatment.

MicroRNAs (miRNAs) are potent modulators of protein expression that play key roles in brain pathways regulating neurogenesis and synaptic plasticity. These small RNAs may be critical for the pathophysiology of mental disorders and may influence the effectiveness of psychotropic drugs. To investigate the possible involvement of miRNAs in the mechanism of action of antidepressants (AD), we conducted a whole-miRNome quantitative analysis with qRT-PCR of the changes in the blood of 10 depressed subjects after 12 weeks of treatment with escitalopram.

myMIR: a genome-wide microRNA targets identification and annotation tool.

miRNA target genes prediction represents a crucial step in miRNAs functional characterization. In this context, the challenging issue remains predictions accuracy and recognition of false positive results. In this article myMIR, a web based system for increasing reliability of miRNAs predicted targets lists, is presented.

Structural and dynamic roles of permanent water molecules in ligand molecular recognition by chicken liver bile acid binding protein.

Chicken liver bile acid binding protein (cL-BABP) crystallizes with water molecules in its binding site. To obtain insights on the role of internal water, we performed two 100 ns molecular dynamics (MD) simulations in explicit solvent for cL-BABP, as apo form and as a complex with two molecules of cholic acid, and analyzed in detail the dynamics properties of all water molecules. The diffusion coefficients of the more persistent internal water molecules are significantly different from the bulk, but similar between the two protein forms.