Reducing Ensembles of Protein Tertiary Structures Generated De Novo via Clustering

Zaman, Ahmed Bin; Kamranfar, Parastoo; Domeniconi, Carlotta; Shehu, Amarda

doi:10.3390/molecules25092228

Cited by 8 publications

(6 citation statements)

References 53 publications

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“…USRs were shown to be highly accurate at describing and comparing molecular shapes. Work in [ 18 ] further showed that USR coordinates were highly useful for low-dimensional representations of protein tertiary structures, and a body of work utilized them to build fast, search space-aware algorithms for exploring and reconstructing the structure space of a protein molecule [ 19 , 20 ], as well as computing motion paths connecting two given structures of a protein molecule [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Fewer Dimensions, More Structures for Improved Discrete Models of Dynamics of Free versus Antigen-Bound Antibody

Kabir

Nussinov

et al. 2022

Biomolecules

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Over the past decade, Markov State Models (MSM) have emerged as powerful methodologies to build discrete models of dynamics over structures obtained from Molecular Dynamics trajectories. The identification of macrostates for the MSM is a central decision that impacts the quality of the MSM but depends on both the selected representation of a structure and the clustering algorithm utilized over the featurized structures. Motivated by a large molecular system in its free and bound state, this paper investigates two directions of research, further reducing the representation dimensionality in a non-parametric, data-driven manner and including more structures in the computation. Rigorous evaluation of the quality of obtained MSMs via various statistical tests in a comparative setting firmly shows that fewer dimensions and more structures result in a better MSM. Many interesting findings emerge from the best MSM, advancing our understanding of the relationship between antibody dynamics and antibody–antigen recognition.

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Section: Introductionmentioning

confidence: 99%

Fewer Dimensions, More Structures for Improved Discrete Models of Dynamics of Free versus Antigen-Bound Antibody

Kabir

Nussinov

et al. 2022

Biomolecules

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“…Using this procedure, the docked ligands, namely, retinol and PS, are ranked according to the docking score. The ligand poses obtained from AutoDock Vina are further analyzed using gmx-cluster algorithm in the GROningen MAchine for Chemical Simulations package . The centroid structures of PS obtained from the gmx-cluster were used as the starting point for the MD simulations.…”

Section: Methodsmentioning

confidence: 99%

Interfacial Interactions between Nanoplastics and Biological Systems: toward an Atomic and Molecular Understanding of Plastics-Driven Biological Dyshomeostasis

Karim,

Yadav,

Sweety

et al. 2024

ACS Appl. Mater. Interfaces

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Micro- and nano-plastics (NPs) are found in human milk, blood, tissues, and organs and associate with aberrant health outcomes including inflammation, genotoxicity, developmental disorders, onset of chronic diseases, and autoimmune disorders. Yet, interfacial interactions between plastics and biomolecular systems remain underexplored. Here, we have examined experimentally, in vitro, in vivo, and by computation, the impact of polystyrene (PS) NPs on a host of biomolecular systems and assemblies. Our results reveal that PS NPs essentially abolished the helix-content of the milk protein β-lactoglobulin (BLG) in a dose-dependent manner. Helix loss is corelated with the near stoichiometric formation of β-sheet elements in the protein. Structural alterations in BLG are also likely responsible for the nanoparticle-dependent attrition in binding affinity and weaker on-rate constant of retinol, its physiological ligand (compromising its nutritional role). PS NP-driven helix-to-sheet conversion was also observed in the amyloid-forming trajectory of hen egg-white lysozyme (accelerated fibril formation and reduced helical content in fibrils). Caenorhabditis elegans exposed to PS NPs exhibited a decrease in the fluorescence of green fluorescent protein-tagged dopaminergic neurons and locomotory deficits (akin to the neurotoxin paraquat exposure). Finally, in silico analyses revealed that the most favorable PS/BLG docking score and binding energies corresponded to a pose near the hydrophobic ligand binding pocket (calyx) of the protein where the NP fragment was found to make nonpolar contacts with side-chain residues via the hydrophobic effect and van der Waals forces, compromising side chain/retinol contacts. Binding energetics indicate that PS/BLG interactions destabilize the binding of retinol to the protein and can potentially displace retinol from the calyx region of BLG, thereby impairing its biological function. Collectively, the experimental and high-resolution in silico data provide new insights into the mechanism(s) by which PS NPs corrupt the bimolecular structure and function, induce amyloidosis and onset neuronal injury, and drive aberrant physiological and behavioral outcomes.

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“…The long-range interactions were treated with the Particle Mesh Ewald (PME) method. The Lennard-Jones potentials were used for van der Waals interactions [ 35 ]. The distance cut-off of 10.0 Å was applied to calculate the nonbond interactions.…”

Section: Methodsmentioning

confidence: 99%

Novel Insights into Understanding the Molecular Dialogues between Bipolaroxin and the Gα and Gβ Subunits of the Wheat Heterotrimeric G-Protein during Host–Pathogen Interaction

et al. 2022

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Spot blotch disease of wheat, caused by the fungus Bipolaris sorokiniana (Sacc.) Shoem., produces several toxins which interact with the plants and thereby increase the blightening of the wheat leaves, and Bipolaroxin is one of them. There is an urgent need to decipher the molecular interaction between wheat and the toxin Bipolaroxin for in-depth understanding of host–pathogen interactions. In the present study, we have developed the three-dimensional structure of G-protein alpha subunit from Triticum aestivum. Molecular docking studies were performed using the active site of the modeled G-protein alpha and cryo-EM structure of beta subunit from T. aestivum and ‘Bipolaroxin’. The study of protein–ligand interactions revealed that six H-bonds are mainly formed by Glu29, Ser30, Lys32, and Ala177 of G-alpha with Bipolaroxin. In the beta subunit, the residues of the core beta strand domain participate in the ligand interaction where Lys256, Phe306, and Leu352 formed seven H-bonds with the ligand Bipolaroxin. All-atoms molecular dynamics (MD) simulation studies were conducted for G-alpha and -beta subunit and Bipolaroxin complexes to explore the stability, conformational flexibility, and dynamic behavior of the complex system. In planta studies clearly indicated that application of Bipolaroxin significantly impacted the physio-biochemical pathways in wheat and led to the blightening of leaves in susceptible cultivars as compared to resistant ones. Further, it interacted with the Gα and Gβ subunits of G-protein, phenylpropanoid, and MAPK pathways, which is clearly supported by the qPCR results. This study gives deeper insights into understanding the molecular dialogues between Bipolaroxin and the Gα and Gβ subunits of the wheat heterotrimeric G-protein during host–pathogen interaction.

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Reducing Ensembles of Protein Tertiary Structures Generated De Novo via Clustering

Cited by 8 publications

References 53 publications

Fewer Dimensions, More Structures for Improved Discrete Models of Dynamics of Free versus Antigen-Bound Antibody

Fewer Dimensions, More Structures for Improved Discrete Models of Dynamics of Free versus Antigen-Bound Antibody

Interfacial Interactions between Nanoplastics and Biological Systems: toward an Atomic and Molecular Understanding of Plastics-Driven Biological Dyshomeostasis

Novel Insights into Understanding the Molecular Dialogues between Bipolaroxin and the Gα and Gβ Subunits of the Wheat Heterotrimeric G-Protein during Host–Pathogen Interaction

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