scholarly journals Ligand Gaussian Accelerated Molecular Dynamics (LiGaMD): Characterization of Ligand Binding Thermodynamics and Kinetics

2020 ◽  
Vol 16 (9) ◽  
pp. 5526-5547 ◽  
Author(s):  
Yinglong Miao ◽  
Apurba Bhattarai ◽  
Jinan Wang
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Binding Thermodynamics ◽  
Accelerated Molecular Dynamics ◽  
Thermodynamics And Kinetics

scholarly journals Ligand Gaussian accelerated molecular dynamics (LiGaMD): Characterization of ligand binding thermodynamics and kinetics

2020 ◽  
Author(s):  
Yinglong Miao ◽  
Apurba Bhattarai ◽  
Jinan Wang
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Ligand Binding ◽  
Free Energies ◽  
Kinetic Rate ◽  
Binding Thermodynamics ◽  
Accelerated Molecular Dynamics ◽  
Thermodynamics And Kinetics ◽  
Kinetic Rate Constants ◽  
Binding Free Energies

AbstractCalculations of ligand binding free energies and kinetic rates are important for drug design. However, such tasks have proven challenging in computational chemistry and biophysics. To address this challenge, we have developed a new computational method “LiGaMD”, which selectively boosts the ligand non-bonded interaction potential energy based on the Gaussian accelerated molecular dynamics (GaMD) enhanced sampling technique. Another boost potential could be applied to the remaining potential energy of the entire system in a dual-boost algorithm (LiGaMD_Dual) to facilitate ligand binding. LiGaMD has been demonstrated on host-guest and protein-ligand binding model systems. Repetitive guest binding and unbinding in the β-cyclodextrin host were observed in hundreds-of-nanosecond LiGaMD simulations. The calculated binding free energies of guest molecules with sufficient sampling agreed excellently with experimental data (< 1.0 kcal/mol error). In comparison with previous microsecond-timescale conventional molecular dynamics simulations, accelerations of ligand kinetic rate constants in LiGaMD simulations were properly estimated using Kramers’ rate theory. Furthermore, LiGaMD allowed us to capture repetitive dissociation and binding of the benzamidine inhibitor in trypsin within 1 μs simulations. The calculated ligand binding free energy and kinetic rate constants compared well with the experimental data. In summary, LiGaMD provides a promising approach for characterizing ligand binding thermodynamics and kinetics simultaneously, which is expected to facilitate computer-aided drug design.

scholarly journals Protein-protein interaction-Gaussian accelerated molecular dynamics (PPI-GaMD): Characterization of protein binding thermodynamics and kinetics

2021 ◽  
Author(s):  
Jinan Wang ◽  
Yinglong Miao
Keyword(s):  
Molecular Dynamics ◽  
Potential Energy ◽  
Protein Binding ◽  
Binding Free Energy ◽  
Model System ◽  
Free Energies ◽  
Binding Thermodynamics ◽  
Accelerated Molecular Dynamics ◽  
Thermodynamics And Kinetics ◽  
Binding Free Energies

Protein-protein interactions (PPIs) play key roles in many fundamental biological processes such as cellular signaling and immune responses. However, it has proven challenging to simulate repetitive protein association and dissociation in order to calculate binding free energies and kinetics of PPIs, due to long biological timescales and complex protein dynamics. To address this challenge, we have developed a new computational approach to all-atom simulations of PPIs based on a robust Gaussian accelerated molecular dynamics (GaMD) technique. The method, termed "PPI-GaMD", selectively boosts interaction potential energy between protein partners to facilitate their slow dissociation. Meanwhile, another boost potential is applied to the remaining potential energy of the entire system to effectively model the protein's flexibility and rebinding. PPI-GaMD has been demonstrated on a model system of the ribonuclease barnase interactions with its inhibitor barstar. Six independent 2 µs PPI-GaMD simulations have captured repetitive barstar dissociation and rebinding events, which enable calculations of the protein binding thermodynamics and kinetics simultaneously. The calculated binding free energies and kinetic rate constants agree well with the experimental data. Furthermore, PPI-GaMD simulations have provided mechanistic insights into barstar binding to barnase, which involve long-range electrostatic interactions and multiple binding pathways, being consistent with previous experimental and computational findings of this model system. In summary, PPI-GaMD provides a highly efficient and easy-to-use approach for binding free energy and kinetics calculations of PPIs.

scholarly journals Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor

2015 ◽  
Vol 48 (4) ◽  
pp. 479-487 ◽  
Author(s):  
Kalli Kappel ◽  
Yinglong Miao ◽  
J. Andrew McCammon
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Partial Agonist ◽  
Md Simulations ◽  
G Protein Coupled Receptor ◽  
Accelerated Molecular Dynamics ◽  
Dynamics Simulations ◽  
G Protein Coupled

AbstractElucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein–ligand binding, especially the drug recognition of GPCRs.

scholarly journals Mode of inhibitory binding of epigallocatechin gallate to the ubiquitin-activating enzyme Uba1 via accelerated molecular dynamics

RSC Advances ◽  
2021 ◽  
Vol 11 (14) ◽  
pp. 8264-8276
Author(s):  
Paras Gaur ◽  
Gabriel Fenteany ◽  
Chetna Tyagi
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Binding Site ◽  
Bond Formation ◽  
Epigallocatechin Gallate ◽  
Accelerated Molecular Dynamics ◽  
Ubiquitin Binding ◽  
Thioester Bond

The hinge-like movement of the SCCH domain upon ligand binding closes the ubiquitin binding site and disrupts the interfaces crucial for thioester bond formation.

Irradiation behavior of pyrolytic silicon carbide

1983 ◽  
Vol 41 ◽  
pp. 72-73
Author(s):  
R. J. Lauf
Keyword(s):  
Silicon Carbide ◽  
Fission Products ◽  
Thermodynamics And Kinetics ◽  
Neutron Fluences ◽  
Fuel Particles ◽  
Sic Coatings ◽  
Irradiation Behavior ◽  
Kinetics Of ◽  
Htgr Fuel

Fuel particles for the High-Temperature Gas-Cooled Reactor (HTGR) contain a layer of pyrolytic silicon carbide to act as a miniature pressure vessel and primary fission product barrier. Optimization of the SiC with respect to fuel performance involves four areas of study: (a) characterization of as-deposited SiC coatings; (b) thermodynamics and kinetics of chemical reactions between SiC and fission products; (c) irradiation behavior of SiC in the absence of fission products; and (d) combined effects of irradiation and fission products. This paper reports the behavior of SiC deposited on inert microspheres and irradiated to fast neutron fluences typical of HTGR fuel at end-of-life.

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