Unveiling the interaction of vanadium compounds with human serum albumin by using 1H STD NMR and computational docking studies

The binding of the VV oxidation products of two vanadium(IV) compounds, [VO(dmpp)2] and [VO(maltolato)2], which have shown promising anti-diabetic properties, to human serum albumin (HSA) in aqueous aerobic solution has been studied by 1H saturation transfer difference (STD) NMR spectroscopy and computational docking studies. Group epitope mapping and docking simulations indicate a preference of HSA binding to the 1:1 [VO2(dmpp)(OH)(H2O)]- and 1:2 [VO 2(maltol)2]- vanadium(V) species. By using known HSA binders, competition NMR experiments revealed that both complexes preferentially bind to drug site I. Docking simulations carried out with HADDOCK together with restraints derived from the STD results led to three-dimensional models that are in agreement with the NMR spectroscopic data, providing useful information on molecular interaction modes. These results indicate that the combination of STD NMR and data-driven docking is a good tool for elucidating the interactions in protein-vanadium compounds and thus for clarifying the mechanism of drug delivery as vanadium compounds have shown potential therapeutic properties. 1H STD NMR analysis complemented by HADDOCK studies have revealed that the [VO2(dmpp)(H2O)(OH)] - species, resulting from the oxidation of the potential insulin mimetic VO(dmpp)2, binds preferentially to HSA site I. These findings corroborate the involvement of this serum protein in the transport of vanadium species in the blood stream and their delivery to target cells

Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5.

The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β2-adrenergic receptor (β2AR). These studies revealed a dynamic mechanism of complex formation that involves large conformational changes in the GRK5 RH/catalytic domain interface upon receptor binding. These changes facilitate contacts between intracellular loops 2 and 3 and the C terminus of the β2AR with the GRK5 RH bundle subdomain, membrane-binding surface, and kinase catalytic cleft, respectively. These studies significantly contribute to our understanding of the mechanism by which GRKs regulate the function of activated GPCRs. PAPERCLIP

Pdb-tools : A swiss army knife for molecular structures [version 1; referees: 2 approved]

The pdb-tools are a collection of Python scripts for working with molecular structure data in the Protein Data Bank (PDB) format. They allow users to edit, convert, and validate PDB files, from the command-line, in a simple but efficient manner. The pdb-tools are implemented in Python, without any external dependencies, and are freely available under the open-source Apache License at https://github.com/haddocking/pdb-tools/ and on PyPI

Pdb-tools: A swiss army knife for molecular structures [version 1; referees: 2 approved]

The pdb-tools are a collection of Python scripts for working with molecular structure data in the Protein Data Bank (PDB) format. They allow users to edit, convert, and validate PDB files, from the command-line, in a simple but efficient manner. The pdb-tools are implemented in Python, without any external dependencies, and are freely available under the open-source Apache License at https://github.com/haddocking/pdb-tools/ and on PyPI

Unveiling the interaction of vanadium compounds with human serum albumin by using 1H STD NMR and computational docking studies

The binding of the VV oxidation products of two vanadium(IV) compounds, [VO(dmpp)2] and [VO(maltolato)2], which have shown promising anti-diabetic properties, to human serum albumin (HSA) in aqueous aerobic solution has been studied by 1H saturation transfer difference (STD) NMR spectroscopy and computational docking studies. Group epitope mapping and docking simulations indicate a preference of HSA binding to the 1:1 [VO2(dmpp)(OH)(H2O)]- and 1:2 [VO 2(maltol)2]- vanadium(V) species. By using known HSA binders, competition NMR experiments revealed that both complexes preferentially bind to drug site I. Docking simulations carried out with HADDOCK together with restraints derived from the STD results led to three-dimensional models that are in agreement with the NMR spectroscopic data, providing useful information on molecular interaction modes. These results indicate that the combination of STD NMR and data-driven docking is a good tool for elucidating the interactions in protein-vanadium compounds and thus for clarifying the mechanism of drug delivery as vanadium compounds have shown potential therapeutic properties. 1H STD NMR analysis complemented by HADDOCK studies have revealed that the [VO2(dmpp)(H2O)(OH)] - species, resulting from the oxidation of the potential insulin mimetic VO(dmpp)2, binds preferentially to HSA site I. These findings corroborate the involvement of this serum protein in the transport of vanadium species in the blood stream and their delivery to target cells

Less Is More: Coarse-Grained Integrative Modeling of Large Biomolecular Assemblies with HADDOCK

Predicting the 3D structure of protein interactions remains a challenge in the field of computational structural biology. This is in part due to difficulties in sampling the complex energy landscape of multiple interacting flexible polypeptide chains. Coarse-graining approaches, which reduce the number of degrees of freedom of the system, help address this limitation by smoothing the energy landscape, allowing an easier identification of the global energy minimum. They also accelerate the calculations, allowing for modeling larger assemblies. Here, we present the implementation of the MARTINI coarse-grained force field for proteins into HADDOCK, our integrative modeling platform. Docking and refinement are performed at the coarse-grained level, and the resulting models are then converted back to atomistic resolution through a distance restraints-guided morphing procedure. Our protocol, tested on the largest complexes of the protein docking benchmark 5, shows an overall ∼7-fold speed increase compared to standard all-atom calculations, while maintaining a similar accuracy and yielding substantially more near-native solutions. To showcase the potential of our method, we performed simultaneous 7 body docking to model the 1:6 KaiC-KaiB complex, integrating mutagenesis and hydrogen/deuterium exchange data from mass spectrometry with symmetry restraints, and validated the resulting models against a recently published cryo-EM structure