scholarly journals Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition

2017 ◽  
Author(s):  
Zhiye Tang ◽  
Chia-en A. Chang
Keyword(s):  
Molecular Recognition ◽  
Force Fields ◽  
Md Simulations ◽  
Dissociation Rate ◽  
Water Molecules ◽  
Practical Applications ◽  
Guest Binding ◽  
Hydrogen Bond Networks ◽  
Comprehensive Picture ◽  
Dissociation Rate Constants

Understanding the fine balance between changes of entropy and enthalpy and the competition between a guest and water molecules in molecular binding is crucial in fundamental studies and practical applications. Experiments provide measurements. However, illustrating the binding/unbinding processes gives a complete picture of molecular recognition not directly available from experiments, and computational methods bridge the gaps. Here, we investigated guest association/dissociation with β-cyclodextrin (β-CD) by using microsecond-timescale molecular dynamics (MD) simulations, post-analysis and numerical calculations. We computed association and dissociation rate constants, enthalpy, and solvent and solute entropy of binding. All the computed values of kon, koff, ΔH, ΔS, and ΔG using GAFF-CD and q4MD-CD force fields for β-CD could be compared with experimental data directly and agreed reasonably with experiment findings. Both force fields resulted in similar computed ΔG from independently computed kinetics rates, ΔG=-RTln(kon · C° / k off), and thermodynamics properties, ΔG=ΔH – TΔS. The water entropy calculations show that entropy gain of desolvating water molecules are a major driving force, and both force fields have the same strength of non-polar attractions between solutes and β-CD as well. Water molecules play a crucial role in guest binding to β-CD. However, collective water/β-CD motions could contribute to different computed kon and ΔH values by different force fields, mainly because the parameters of β-CD provide different motions of β-CD, hydrogen-bond networks of water molecules in the cavity of free β-CD and the strength of desolvation penalty. As a result, q4MD-CD suggests that guest binding is mostly driven by enthalpy, while GAFF-CD shows that gaining entropy is the major driven force of binding. The study further interprets experiments, deepens our understanding of ligand binding, and suggests strategies for force field parameterization.

Characterizing the Water Wire in the Gramicidin Channel Found by Monte Carlo Sampling Using Continuum Electrostatics and in Molecular Dynamics Trajectories with Conventional or Polarizable Force Fields

2020 ◽  
pp. 1-20
Author(s):  
Yingying Zhang ◽  
Kamran Haider ◽  
Divya Kaur ◽  
Van A. Ngo ◽  
Xiuhong Cai ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Dipole Moment ◽  
Electrostatic Interactions ◽  
Hybrid Methods ◽  
Force Fields ◽  
Proton Channel ◽  
Water Molecules ◽  
Implicit Solvent ◽  
Continuum Electrostatics ◽  
Hydrogen Bond Networks

Water molecules play a key role in all biochemical processes. They help define the shape of proteins, and they are reactant or product in many reactions and are released as ligands are bound. They facilitate the transfer of protons through transmembrane proton channel, pump and transporter proteins. Continuum electrostatics (CE) force fields used by program Multiconformation CE (MCCE) capture electrostatic interactions in biomolecules with an implicit solvent, which captures the averaged solvent water equilibrium properties. Hybrid CE methods can use explicit water molecules within the protein surrounded by implicit solvent. These hybrid methods permit the study of explicit hydrogen bond networks within the protein and allow analysis of processes such as proton transfer reactions. Yet hybrid CE methods have not been rigorously tested. Here, we present an explicit treatment of water molecules in the Gramicidin A (gA) channel using MCCE and compare the resulting distributions of water molecules and key hydration features against those obtained with explicit solvent Molecular Dynamics (MD) simulations with the nonpolarizable CHARMM36 and polarizable Drude force fields. CHARMM36 leads to an aligned water wire in the channel characterized by a large absolute net water dipole moment; the MCCE and Drude analysis lead to a small net dipole moment as the water molecules change orientation within the channel. The correct orientation is not as yet known, so these calculations identify an open question.

Characterizing the water wire in the Gramicidin channel found by Monte Carlo sampling using continuum electrostatics and in molecular dynamics trajectories with conventional or polarizable force fields

2020 ◽  
pp. 2042001
Author(s):  
Yingying Zhang ◽  
Kamran Haider ◽  
Divya Kaur ◽  
Van A. Ngo ◽  
Xiuhong Cai ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Dipole Moment ◽  
Electrostatic Interactions ◽  
Hybrid Methods ◽  
Force Fields ◽  
Proton Channel ◽  
Water Molecules ◽  
Implicit Solvent ◽  
Continuum Electrostatics ◽  
Hydrogen Bond Networks

Water molecules play a key role in all biochemical processes. They help define the shape of proteins, and they are reactant or product in many reactions and are released as ligands are bound. They facilitate the transfer of protons through transmembrane proton channel, pump and transporter proteins. Continuum electrostatics (CE) force fields used by program Multiconformation CE (MCCE) capture electrostatic interactions in biomolecules with an implicit solvent, which captures the averaged solvent water equilibrium properties. Hybrid CE methods can use explicit water molecules within the protein surrounded by implicit solvent. These hybrid methods permit the study of explicit hydrogen bond networks within the protein and allow analysis of processes such as proton transfer reactions. Yet hybrid CE methods have not been rigorously tested. Here, we present an explicit treatment of water molecules in the Gramicidin A (gA) channel using MCCE and compare the resulting distributions of water molecules and key hydration features against those obtained with explicit solvent Molecular Dynamics (MD) simulations with the nonpolarizable CHARMM36 and polarizable Drude force fields. CHARMM36 leads to an aligned water wire in the channel characterized by a large absolute net water dipole moment; the MCCE and Drude analysis lead to a small net dipole moment as the water molecules change orientation within the channel. The correct orientation is not as yet known, so these calculations identify an open question.

Temperature Dependence of the Air/Water Interface Revealed by Polarization Sensitive Sum-Frequency Generation Spectroscopy

2018 ◽  
Author(s):  
Daniel R. Moberg ◽  
Shelby C. Straight ◽  
Francesco Paesani
Keyword(s):  
Temperature Dependence ◽  
Low Frequency ◽  
Potential Energy Function ◽  
Md Simulations ◽  
Sum Frequency Generation ◽  
Water Molecules ◽  
Water Interface ◽  
Sum Frequency ◽  
Air Water Interface ◽  
Frequency Generation

<div> <div> <div> <p>The temperature dependence of the vibrational sum-frequency generation (vSFG) spectra of the the air/water interface is investigated using many-body molecular dynamics (MB-MD) simulations performed with the MB-pol potential energy function. The total vSFG spectra calculated for different polarization combinations are then analyzed in terms of molecular auto-correlation and cross-correlation contributions. To provide molecular-level insights into interfacial hydrogen-bonding topologies, which give rise to specific spectroscopic features, the vSFG spectra are further investigated by separating contributions associated with water molecules donating 0, 1, or 2 hydrogen bonds to neighboring water molecules. This analysis suggests that the low frequency shoulder of the free OH peak which appears at ∼3600 cm−1 is primarily due to intermolecular couplings between both singly and doubly hydrogen-bonded molecules. </p> </div> </div> </div>

High proton conductivity in a nickel(ii) complex and its hybrid membrane

2019 ◽  
Vol 48 (6) ◽  
pp. 2190-2196 ◽  
Author(s):  
Shuai-Liang Yang ◽  
Yue-Ying Yuan ◽  
Fei Ren ◽  
Chen-Xi Zhang ◽  
Qing-Lun Wang
Keyword(s):  
Hydrogen Bond ◽  
Proton Conductivity ◽  
Hybrid Membrane ◽  
Water Molecules ◽  
Hybrid Membranes ◽  
High Proton Conductivity ◽  
High Proton ◽  
Hydrogen Bond Networks

A novel 2D nickel(ii) complex (1) has been successfully synthesized using a 2,2′-bipyridyl, polycarboxylsulfonate ligand H4SBTC and Ni2+ ions. Owing to the presence of abundant water molecules, hydrogen bond networks and other protons, 1 and its hybrid membranes demonstrate high proton conductivity.

scholarly journals High-resolution mining of the SARS-CoV-2 main protease conformational space: supercomputer-driven unsupervised adaptive sampling

2021 ◽  
Author(s):  
Théo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Olivier Adjoua ◽  
Dina El Ahdab ◽  
Luc-Henri Jolly ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
High Resolution ◽  
Adaptive Sampling ◽  
Force Fields ◽  
Sampling Strategy ◽  
Md Simulations ◽  
Conformational Space ◽  
Many Body ◽  
Polarizable Force Fields ◽  
Main Protease

We provide an unsupervised adaptive sampling strategy capable of producing μs-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFFs).

Structural and dynamic roles of permanent water molecules in ligand molecular recognition by chicken liver bile acid binding protein

2008 ◽  
Vol 21 (5) ◽  
pp. 348-354 ◽  
Author(s):  
Piero Ricchiuto ◽  
Alessandro Guerini Rocco ◽  
Elisabetta Gianazza ◽  
Dario Corrada ◽  
Tiziana Beringhelli ◽  
...  
Keyword(s):  
Bile Acid ◽  
Molecular Recognition ◽  
Binding Protein ◽  
Chicken Liver ◽  
Water Molecules ◽  
Acid Binding Protein ◽  
Bile Acid Binding

scholarly journals Desensitization Contributes to the Synaptic Response of Gain-of-Function Mutants of the Muscle Nicotinic Receptor

2006 ◽  
Vol 128 (5) ◽  
pp. 615-627 ◽  
Author(s):  
Sergio Elenes ◽  
Ying Ni ◽  
Gisela D. Cymes ◽  
Claudio Grosman
Keyword(s):  
Nicotinic Receptor ◽  
Dissociation Rate ◽  
Gain Of Function ◽  
Naturally Occurring ◽  
Channel Opening ◽  
Speed Up ◽  
High Concentrations ◽  
Dissociation Rate Constants ◽  
Kinetics Of ◽  
Peak Value

Although the muscle nicotinic receptor (AChR) desensitizes almost completely in the steady presence of high concentrations of acetylcholine (ACh), it is well established that AChRs do not accumulate in desensitized states under normal physiological conditions of neurotransmitter release and clearance. Quantitative considerations in the framework of plausible kinetic schemes, however, lead us to predict that mutations that speed up channel opening, slow down channel closure, and/or slow down the dissociation of neurotransmitter (i.e., gain-of-function mutations) increase the extent to which AChRs desensitize upon ACh removal. In this paper, we confirm this prediction by applying high-frequency trains of brief (∼1 ms) ACh pulses to outside-out membrane patches expressing either lab-engineered or naturally occurring (disease-causing) gain-of-function mutants. Entry into desensitization was evident in our experiments as a frequency-dependent depression in the peak value of succesive macroscopic current responses, in a manner that is remarkably consistent with the theoretical expectation. We conclude that the comparatively small depression of the macroscopic currents observed upon repetitive stimulation of the wild-type AChR is due, not to desensitization being exceedingly slow but, rather, to the particular balance between gating, entry into desensitization, and ACh dissociation rate constants. Disruption of this fine balance by, for example, mutations can lead to enhanced desensitization even if the kinetics of entry into, and recovery from, desensitization themselves are not affected. It follows that accounting for the (usually overlooked) desensitization phenomenon is essential for the correct interpretation of mutagenesis-driven structure–function relationships and for the understanding of pathological synaptic transmission at the vertebrate neuromuscular junction.

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