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1.
Methods Mol Biol ; 2340: 105-120, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35167072

RESUMEN

We review the contact-based description of aggregation of intrinsically disordered proteins in coarse-grained and all-atom models. We consider polyglutamines and polyalanines at various concentrations of the peptides. We also study associations of two chains of α-synuclein and up to 20 chains of a 12-residue-long segment of protein tau. We demonstrate that the total number of two-chain association events (in an aggregate that comprises at least two chains) provides a useful measure of the propensity to aggregate. This measure is consistent, for instance, with the previously reported mass spectroscopy data. The distribution of the number of association events is given essentially by a power law as a function of the duration of these events. The corresponding exponent depends on the protein and the temperature but not on the concentration of the proteins.


Asunto(s)
Proteínas Intrínsecamente Desordenadas , Simulación de Dinámica Molecular , Conformación Proteica , alfa-Sinucleína , Proteínas tau
2.
Sci Rep ; 11(1): 11144, 2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-34045551

RESUMEN

E. coli purine nucleoside phosphorylase is a homohexamer, which structure, in the apo form, can be described as a trimer of dimers. Earlier studies suggested that ligand binding and kinetic properties are well described by two binding constants and two sets of kinetic constants. However, most of the crystal structures of this enzyme complexes with ligands do not hold the three-fold symmetry, but only two-fold symmetry, as one of the three dimers is different (both active sites in the open conformation) from the other two (one active site in the open and one in the closed conformation). Our recent detailed studies conducted over broad ligand concentration range suggest that protein-ligand complex formation in solution actually deviates from the two-binding-site model. To reveal the details of interactions present in the hexameric molecule we have engineered a single tryptophan Y160W mutant, responding with substantial intrinsic fluorescence change upon ligand binding. By observing various physical properties of the protein and its various complexes with substrate and substrate analogues we have shown that indeed three-binding-site model is necessary to properly describe binding of ligands by both the wild type enzyme and the Y160W mutant. Thus we have pointed out that a symmetrical dimer with both active sites in the open conformation is not forced to adopt this conformation by interactions in the crystal, but most probably the dimers forming the hexamer in solution are not equivalent as well. This, in turn, implies that an allosteric cooperation occurs not only within a dimer, but also among all three dimers forming a hexameric molecule.


Asunto(s)
Escherichia coli/genética , Mutación , Purina-Nucleósido Fosforilasa/genética , Triptófano/genética , Sitios de Unión , Escherichia coli/metabolismo , Modelos Moleculares , Conformación Proteica , Purina-Nucleósido Fosforilasa/metabolismo
3.
PLoS Comput Biol ; 17(3): e1008840, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33760823

RESUMEN

Wheat (Triticum spp.) gluten consists mainly of intrinsincally disordered storage proteins (glutenins and gliadins) that can form megadalton-sized networks. These networks are responsible for the unique viscoelastic properties of wheat dough and affect the quality of bread. These properties have not yet been studied by molecular level simulations. Here, we use a newly developed α-C-based coarse-grained model to study ∼ 4000-residue systems. The corresponding time-dependent properties are studied through shear and axial deformations. We measure the response force to the deformation, the number of entanglements and cavities, the mobility of residues, the number of the inter-chain bonds, etc. Glutenins are shown to influence the mechanics of gluten much more than gliadins. Our simulations are consistent with the existing ideas about gluten elasticity and emphasize the role of entanglements and hydrogen bonding. We also demonstrate that the storage proteins in maize and rice lead to weaker elasticity which points to the unique properties of wheat gluten.


Asunto(s)
Glútenes , Triticum/química , Biología Computacional , Elasticidad/fisiología , Glútenes/química , Glútenes/fisiología , Simulación de Dinámica Molecular , Viscosidad
4.
Prog Mol Biol Transl Sci ; 174: 79-103, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32828471

RESUMEN

We provide a brief overview of the topological features found in structured proteins and of the dynamical processes that involve knots. We then discuss the knotted states that arise in the intrinsically disordered polyglutamine and α-synuclein. We argue that the existence of the knotted conformations stalls degradation by proteases and thus enhances aggregation. This mechanism works if the length of a peptide chain exceeds a threshold, as in the Huntington disease. We also study the cavities that form within the conformations of the disordered proteins. The volume of the cavities varies in time in a way that is different than that of the radius of gyration or the end-to-end distance. In addition, we study the traffic between the conformational basins and identify patterns associated with the deep and shallow knots. The results are obtained by molecular dynamics simulations that use coarse-grained and all-atom models (with and without the explicit solvent).


Asunto(s)
Proteínas Intrínsecamente Desordenadas/química , Degeneración Nerviosa/patología , Animales , Humanos , Modelos Moleculares , Péptidos/química , Conformación Proteica , Proteolisis
5.
Phys Chem Chem Phys ; 22(27): 15592-15599, 2020 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-32613961

RESUMEN

In order to gain insight into the formation of proteinaceous liquid droplets, we study systems of many disordered homopeptide chains within our coarse-grained molecular dynamics model with conformation-dependent terms. We construct the phase diagrams for polyalanine of length 20 and polyglutamines of lengths 20, 40 and 60 based on the stationary-state cluster distribution. The phase diagrams are distinct but correspond to the same topology. We delineate the liquid-gas coexistence curve at around room temperature. We also identify a novel amyloid glass phase that is substantially cross linked forming amorphous and anisotropic spatial patterns. Generally, this phase is found at lower temperatures, but may also appear at room temperature for sufficiently long chains. We demonstrate the existence of fluid-like phenomena, like droplet fusion and fission. However, our available length scales have not yet shown the validity of the continuum physics description.


Asunto(s)
Amiloide/química , Proteínas Intrínsecamente Desordenadas/química , Vidrio/química , Modelos Moleculares , Transición de Fase , Agregado de Proteínas
6.
Phys Chem Chem Phys ; 20(28): 19057-19070, 2018 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-29972174

RESUMEN

We construct a one-bead-per-residue coarse-grained dynamical model to describe intrinsically disordered proteins at significantly longer timescales than in the all-atom models. In this model, inter-residue contacts form and disappear during the course of the time evolution. The contacts may arise between the sidechains, the backbones or the sidechains and backbones of the interacting residues. The model yields results that are consistent with many all-atom and experimental data on these systems. We demonstrate that the geometrical properties of various homopeptides differ substantially in this model. In particular, the average radius of gyration scales with the sequence length in a residue-dependent manner.


Asunto(s)
Proteínas Intrínsecamente Desordenadas/química , Modelos Químicos , Péptidos/química , Conformación Proteica
7.
Proteins ; 82(11): 3144-53, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25142868

RESUMEN

Using coarse-grained molecular dynamics simulations, we analyze mechanically induced dissociation and unfolding of the protein complex CD48-2B4. This heterodimer is an indispensable component of the immunological system: 2B4 is a receptor on natural killer cells whereas CD48 is expressed on surfaces of various immune cells. So far, its mechanostability has not been assessed either experimentally or theoretically. We find that the dissociation processes strongly depend on the direction of pulling and may take place in several pathways. Interestingly, the CD48-2B4 interface can be divided into three distinct patches that act as units when resisting the pulling forces. At experimentally accessible pulling speeds, the characteristic mechanostability forces are in the range between 100 and 200 pN, depending on the pulling direction. These characteristic forces need not be associated with tensile forces involved in the act of separation of the complex because prior shear-involving unraveling within individual proteins may give rise to a higher force peak.


Asunto(s)
Antígenos CD/química , Desplegamiento Proteico , Receptores Inmunológicos/química , Antígenos CD/metabolismo , Antígeno CD48 , Modelos Moleculares , Simulación de Dinámica Molecular , Complejos Multiproteicos/química , Estructura Terciaria de Proteína , Receptores Inmunológicos/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Sinaptotagmina I/química
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