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Design of Potent and Controllable Anticoagulants Using DNA Aptamers and Nanostructures

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      Abstract

      The regulation of thrombin activity offers an opportunity to regulate blood clotting because of the central role played by this molecule in the coagulation cascade. Thrombin-binding DNA aptamers have been used to inhibit thrombin activity. In the past, to address the low efficacy reported for these aptamers during clinical trials, multiple aptamers have been linked using DNA nanostructures. Here, we modify that strategy by linking multiple copies of various thrombin-binding aptamers using DNA weave tiles. The resulting constructs have very high anticoagulant activity in functional assays owing to their improved cooperative binding affinity to thrombin due to optimized spacing, orientation, and the high local concentration of aptamers. We also report the results of molecular dynamics simulations to gain insight into the solution conformations of the tiles. Moreover, by using DNA strand displacement, we were able to turn the coagulation cascade off and on as desired, thereby enabling significantly better control over blood coagulation.

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      Most cited references 31

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      Electrostatics of nanosystems: application to microtubules and the ribosome.

      Evaluation of the electrostatic properties of biomolecules has become a standard practice in molecular biophysics. Foremost among the models used to elucidate the electrostatic potential is the Poisson-Boltzmann equation; however, existing methods for solving this equation have limited the scope of accurate electrostatic calculations to relatively small biomolecular systems. Here we present the application of numerical methods to enable the trivially parallel solution of the Poisson-Boltzmann equation for supramolecular structures that are orders of magnitude larger in size. As a demonstration of this methodology, electrostatic potentials have been calculated for large microtubule and ribosome structures. The results point to the likely role of electrostatics in a variety of activities of these structures.
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        PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations.

        Continuum solvation models, such as Poisson-Boltzmann and Generalized Born methods, have become increasingly popular tools for investigating the influence of electrostatics on biomolecular structure, energetics and dynamics. However, the use of such methods requires accurate and complete structural data as well as force field parameters such as atomic charges and radii. Unfortunately, the limiting step in continuum electrostatics calculations is often the addition of missing atomic coordinates to molecular structures from the Protein Data Bank and the assignment of parameters to biomolecular structures. To address this problem, we have developed the PDB2PQR web service (http://agave.wustl.edu/pdb2pqr/). This server automates many of the common tasks of preparing structures for continuum electrostatics calculations, including adding a limited number of missing heavy atoms to biomolecular structures, estimating titration states and protonating biomolecules in a manner consistent with favorable hydrogen bonding, assigning charge and radius parameters from a variety of force fields, and finally generating 'PQR' output compatible with several popular computational biology packages. This service is intended to facilitate the setup and execution of electrostatics calculations for both experts and non-experts and thereby broaden the accessibility to the biological community of continuum electrostatics analyses of biomolecular systems.
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          PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations

          Real-world observable physical and chemical characteristics are increasingly being calculated from the 3D structures of biomolecules. Methods for calculating pK a values, binding constants of ligands, and changes in protein stability are readily available, but often the limiting step in computational biology is the conversion of PDB structures into formats ready for use with biomolecular simulation software. The continued sophistication and integration of biomolecular simulation methods for systems- and genome-wide studies requires a fast, robust, physically realistic and standardized protocol for preparing macromolecular structures for biophysical algorithms. As described previously, the PDB2PQR web server addresses this need for electrostatic field calculations (Dolinsky et al., Nucleic Acids Research, 32, W665–W667, 2004). Here we report the significantly expanded PDB2PQR that includes the following features: robust standalone command line support, improved pKa estimation via the PROPKA framework, ligand parameterization via PEOE_PB charge methodology, expanded set of force fields and easily incorporated user-defined parameters via XML input files, and improvement of atom addition and optimization code. These features are available through a new web interface (http://pdb2pqr.sourceforge.net/), which offers users a wide range of options for PDB file conversion, modification and parameterization.
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            Author and article information

            Affiliations
            [1 ]Department of Materials Science and Engineering, College of Engineering, North Carolina State University, Raleigh, NC 27695, USA; abhi1jit@ 123456gmail.com (A.R.); janash@ 123456ncsu.edu (J.A.N.); yara_yingling@ 123456ncsu.edu (Y.G.Y.)
            [2 ]Department of Molecular and Structural Biochemistry, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC 27695, USA; bgoodfred@ 123456gmail.com
            Author notes
            [* ]Correspondence: thlabean@ 123456ncsu.edu ; Tel.: +1-919-515-2204
            [†]

            Present address: Department of Chemistry, College of Science, Marshall University, Huntington, WV 25755, USA.

            Contributors
            Role: Academic Editor
            Journal
            Molecules
            Molecules
            molecules
            Molecules
            MDPI
            1420-3049
            06 February 2016
            February 2016
            : 21
            : 2
            26861277
            6273181
            10.3390/molecules21020202
            molecules-21-00202
            (Academic Editor)
            © 2016 by the authors.

            Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

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