The Experts below are selected from a list of 5178 Experts worldwide ranked by ideXlab platform
Arthur Christopoulos - One of the best experts on this subject based on the ideXlab platform.
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Structural Basis for Binding of Allosteric Drug Leads in the Adenosine A_1 Receptor
Scientific Reports, 2018Co-Authors: Yinglong Miao, Apurba Bhattarai, Anh T. N. Nguyen, Arthur ChristopoulosAbstract:Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A_1 receptor (A_1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A_1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A_1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 Å away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A_1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A_1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A_1AR, which will greatly facilitate the receptor structure-based drug design.
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structural basis for binding of allosteric drug leads in the adenosine a1 receptor
Scientific Reports, 2018Co-Authors: Yinglong Miao, Apurba Bhattarai, Anh T. N. Nguyen, Arthur ChristopoulosAbstract:Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A1 receptor (A1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 A away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A1AR, which will greatly facilitate the receptor structure-based drug design.
Yinglong Miao - One of the best experts on this subject based on the ideXlab platform.
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structural basis for binding of allosteric drug leads in the adenosine a1 receptor
Scientific Reports, 2018Co-Authors: Yinglong Miao, Apurba Bhattarai, Anh T. N. Nguyen, Arthur ChristopoulosAbstract:Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A1 receptor (A1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 A away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A1AR, which will greatly facilitate the receptor structure-based drug design.
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Structural Basis for Binding of Allosteric Drug Leads in the Adenosine A_1 Receptor
Scientific Reports, 2018Co-Authors: Yinglong Miao, Apurba Bhattarai, Anh T. N. Nguyen, Arthur ChristopoulosAbstract:Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A_1 receptor (A_1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A_1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A_1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 Å away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A_1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A_1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A_1AR, which will greatly facilitate the receptor structure-based drug design.
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Gaussian Accelerated Molecular Dynamics in NAMD
Journal of chemical theory and computation, 2016Co-Authors: Yui Tik Pang, Yinglong Miao, Yi Wang, J. Andrew MccammonAbstract:Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that provides efficient free energy calculations of biomolecules. Like the previous accelerated molecular dynamics (aMD), GaMD allows for “unconstrained” enhanced sampling without the need to set predefined collective variables and so is useful for studying complex biomolecular conformational changes such as protein folding and ligand binding. Furthermore, because the boost potential is constructed using a harmonic function that follows Gaussian distribution in GaMD, cumulant expansion to the second order can be applied to recover the original free energy profiles of proteins and other large biomolecules, which solves a long-standing energetic reweighting problem of the previous aMD method. Taken together, GaMD offers major advantages for both unconstrained enhanced sampling and free energy calculations of large biomolecules. Here, we have implemented GaMD in the NAMD package on top of the existing aMD featu...
Anh T. N. Nguyen - One of the best experts on this subject based on the ideXlab platform.
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Structural Basis for Binding of Allosteric Drug Leads in the Adenosine A_1 Receptor
Scientific Reports, 2018Co-Authors: Yinglong Miao, Apurba Bhattarai, Anh T. N. Nguyen, Arthur ChristopoulosAbstract:Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A_1 receptor (A_1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A_1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A_1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 Å away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A_1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A_1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A_1AR, which will greatly facilitate the receptor structure-based drug design.
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structural basis for binding of allosteric drug leads in the adenosine a1 receptor
Scientific Reports, 2018Co-Authors: Yinglong Miao, Apurba Bhattarai, Anh T. N. Nguyen, Arthur ChristopoulosAbstract:Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A1 receptor (A1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 A away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A1AR, which will greatly facilitate the receptor structure-based drug design.
Apurba Bhattarai - One of the best experts on this subject based on the ideXlab platform.
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Structural Basis for Binding of Allosteric Drug Leads in the Adenosine A_1 Receptor
Scientific Reports, 2018Co-Authors: Yinglong Miao, Apurba Bhattarai, Anh T. N. Nguyen, Arthur ChristopoulosAbstract:Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A_1 receptor (A_1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A_1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A_1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 Å away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A_1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A_1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A_1AR, which will greatly facilitate the receptor structure-based drug design.
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structural basis for binding of allosteric drug leads in the adenosine a1 receptor
Scientific Reports, 2018Co-Authors: Yinglong Miao, Apurba Bhattarai, Anh T. N. Nguyen, Arthur ChristopoulosAbstract:Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A1 receptor (A1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 A away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A1AR, which will greatly facilitate the receptor structure-based drug design.
Klaus Schulten - One of the best experts on this subject based on the ideXlab platform.
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Scalable molecular dynamics with NAMD
Journal of Computational Chemistry, 2005Co-Authors: James C. Phillips, James Gumbart, Elizabeth Villa, Laxmikant Kalé, Rosemary Braun, Robert D. Skeel, Emad Tajkhorshid, Christophe Chipot, Wei Wang, Klaus SchultenAbstract:NAMD is a parallel molecular dynamics code designed for high-performance simulation of large biomolecular systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This article, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical molecular dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temperature and pressure controls used. Features for steering the simulation across barriers and for calculating both alchemical and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Finally, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomolecular system, highlighting particular features of NAMD, for example, the Tcl scripting language. The article also provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the molecular graphics/sequence analysis software VMD and the grid computing/collaboratory software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.
