Dataset Information

Electrostatics of Tau Protein by Molecular Dynamics.

ABSTRACT: Tau is a microtubule-associated protein that promotes microtubule assembly and stability. This protein is implicated in several neurodegenerative diseases, including Alzheimer's. To date, the three-dimensional (3D) structure of tau has not been fully solved, experimentally. Even the most recent information is sometimes controversial in regard to how this protein folds, interacts, and behaves. Predicting the tau structure and its profile sheds light on the knowledge about its properties and biological function, such as the binding to microtubules (MT) and, for instance, the effect on ionic conductivity. Our findings on the tau structure suggest a disordered protein, with discrete portions of well-defined secondary structure, mostly at the microtubule binding region. In addition, the first molecular dynamics simulation of full-length tau along with an MT section was performed, unveiling tau structure when associated with MT and interaction sites. Electrostatics and conductivity were also examined to understand how tau affects the ions in the intracellular fluid environment. Our results bring a new insight into tau and tubulin MT proteins, their characteristics, and the structure?function relationship.

SUBMITTER: Castro TG

PROVIDER: S-EPMC6468555 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Electrostatics of Tau Protein by Molecular Dynamics.

Castro Tarsila G TG Munteanu Florentina-Daniela FD Cavaco-Paulo Artur A

Biomolecules 20190323 3

Tau is a microtubule-associated protein that promotes microtubule assembly and stability. This protein is implicated in several neurodegenerative diseases, including Alzheimer's. To date, the three-dimensional (3D) structure of tau has not been fully solved, experimentally. Even the most recent information is sometimes controversial in regard to how this protein folds, interacts, and behaves. Predicting the tau structure and its profile sheds light on the knowledge about its properties and biolo ...[more]

PMID: 30909607

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Project description:Microtubule-associated protein (MAP) tau is a cross-linking molecule that provides structural stability to axonal microtubules (MT). It is considered a potential biomarker for Alzheimer's disease (AD), dementia, and other neurological disorders. It is also a signature protein for Traumatic Brain Injury (TBI) assessment. In the case of TBI, extreme dynamic mechanical energies can be felt by the axonal cytoskeletal members. As such, fundamental understandings of the responses of single tau protein, polymerized tau protein, and tau-microtubule interfaces under high-rate mechanical forces are important. This study attempts to determine the high-strain rate mechanical behavior of single tau, dimerized tau, and tau-MT interface using molecular dynamics (MD) simulation. The results show that a single tau protein is a highly stretchable soft polymer. During deformation, first, it significantly unfolds against van der Waals and electrostatic bonds. Then it stretches against strong covalent bonds. We found that tau acts as a viscoelastic material, and its stiffness increases with the strain rate. The unfolding stiffness can be ~50-500 MPa, while pure stretching stiffness can be >2 GPa. The dimerized tau model exhibits similar behavior under similar strain rates, and tau sliding from another tau is not observed until it is stretched to >7 times of original length, depending on the strain rate. The tau-MT interface simulations show that very high strain and strain rates are required to separate tau from MT suggesting Tau-MT bonding is stronger than MT subunit bonding between themselves. The dimerized tau-MT interface simulations suggest that tau-tau bonding is stronger than tau-MT bonding. In summary, this study focuses on the structural response of individual cytoskeletal components, namely microtubule (MT) and tau protein. Furthermore, we consider not only the individual response of a component, but also their interaction with each other (such as tau with tau or tau with MT). This study will eventually pave the way to build a bottom-up multiscale brain model and analyze TBI more comprehensively.

Project description:The proteins of the pancreatic ribonuclease A (RNase A) family catalyze the cleavage of the RNA polymer chain. The development of RNase inhibitors is of significant interest, as some of these compounds may have a therapeutic effect in pathological conditions associated with these proteins. The most potent low molecular weight inhibitor of RNase reported to date is the compound 5'-phospho-2'-deoxyuridine-3-pyrophosphate (P-->5)-adenosine-3-phosphate (pdUppA-3'-p). The 3',5'-pyrophosphate group of this compound increases its affinity and introduces structural features which seem to be unique in pyrophosphate-containing ligands bound to RNase A, such as the adoption of a syn conformation by the adenosine base at RNase subsite B(2) and the placement of the 5'-beta-phosphate of the adenylate (instead of the alpha-phosphate) at subsite P(1) where the phosphodiester bond cleavage occurs. In this work, we study by multi-ns molecular dynamics simulations the structural properties of RNase A complexes with the ligand pdUppA-3'-p and the related weaker inhibitor dUppA, which lacks the 3' and 5' terminal phosphate groups of pdUppA-3'-p. The simulations show that the adenylate 5'-beta-phosphate binding position and the adenosine syn orientation constitute robust structural features in both complexes, stabilized by persistent interactions with specific active-site residues of subsites P(1) and B(2). The simulation structures are used in conjunction with a continuum-electrostatics (Poisson-Boltzmann) model, to evaluate the relative binding affinity of the two complexes. The computed relative affinity of pdUppA-3'-p varies between -7.9 kcal/mol and -2.8 kcal/mol for a range of protein/ligand dielectric constants (epsilon(p)) 2-20, in good agreement with the experimental value (-3.6 kcal/mol); the agreement becomes exact with epsilon(p) = 8. The success of the continuum-electrostatics model suggests that the differences in affinity of the two ligands originate mainly from electrostatic interactions. A residue decomposition of the electrostatic free energies shows that the terminal phosphate groups of pdUppA-3'-p make increased interactions with residues Lys(7) and Lys(66) of the more remote sites P(2) and P(0), and His(119) of site P(1).

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Electrostatics of Tau Protein by Molecular Dynamics.

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Electrostatics of Tau Protein by Molecular Dynamics.

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