scholarly journals Energy penalties enhance flexible receptor docking in a model cavity

2021 ◽  
Vol 118 (36) ◽  
pp. e2106195118
Author(s):  
Anna S. Kamenik ◽  
Isha Singh ◽  
Parnian Lak ◽  
Trent E. Balius ◽  
Klaus R. Liedl ◽  
...  
Keyword(s):  
Protein Flexibility ◽  
Md Simulations ◽  
High Energy ◽  
General Applicability ◽  
Penalty Term ◽  
Conformational Ensembles ◽  
X Ray Crystallography ◽  
Conformational Preferences ◽  
Energy Penalty ◽  
Cavity Opening

Protein flexibility remains a major challenge in library docking because of difficulties in sampling conformational ensembles with accurate probabilities. Here, we use the model cavity site of T4 lysozyme L99A to test flexible receptor docking with energy penalties from molecular dynamics (MD) simulations. Crystallography with larger and smaller ligands indicates that this cavity can adopt three major conformations: open, intermediate, and closed. Since smaller ligands typically bind better to the cavity site, we anticipate an energy penalty for the cavity opening. To estimate its magnitude, we calculate conformational preferences from MD simulations. We find that including a penalty term is essential for retrospective ligand enrichment; otherwise, high-energy states dominate the docking. We then prospectively docked a library of over 900,000 compounds for new molecules binding to each conformational state. Absent a penalty term, the open conformation dominated the docking results; inclusion of this term led to a balanced sampling of ligands against each state. High ranked molecules were experimentally tested by Tm upshift and X-ray crystallography. From 33 selected molecules, we identified 18 ligands and determined 13 crystal structures. Most interesting were those bound to the open cavity, where the buried site opens to bulk solvent. Here, highly unusual ligands for this cavity had been predicted, including large ligands with polar tails; these were confirmed both by binding and by crystallography. In docking, incorporating protein flexibility with thermodynamic weightings may thus access new ligand chemotypes. The MD approach to accessing and, crucially, weighting such alternative states may find general applicability.

scholarly journals Energy Penalties Enhance Flexible Receptor Docking in a Model Cavity

2021 ◽  
Author(s):  
Anna Sophia Kamenik ◽  
Isha Singh ◽  
Parnian Lak ◽  
Trent E Balius ◽  
Klaus R Liedl ◽  
...  
Keyword(s):  
Protein Flexibility ◽  
Md Simulations ◽  
High Energy ◽  
General Applicability ◽  
Penalty Term ◽  
Conformational Ensembles ◽  
X Ray Crystallography ◽  
Conformational Preferences ◽  
Energy Penalty ◽  
Cavity Opening

Protein flexibility remains a major challenge in library docking due to difficulties in sampling conformational ensembles with accurate probabilities. Here we use the model cavity site of T4 Lysozyme L99A to test flexible receptor docking with energy penalties from molecular dynamics (MD) simulations. Crystallography with larger and smaller ligands indicates that this cavity can adopt three major conformations, open, intermediate, and closed. Since smaller ligands typically bind better to the cavity site, we anticipate an energy penalty for cavity opening. To estimate its magnitude, we calculate conformational preferences from MD simulations. We find that including a penalty term is essential for retrospective ligand enrichment, otherwise high-energy states dominate the docking. We then prospectively docked a library of over 900,000 compounds for new molecules binding to each conformational state. Absent a penalty term, the open conformation dominated the docking results; inclusion of this term led to a balanced sampling of ligands against each state. High ranked molecules were experimentally tested by Tm-upshift and X-ray crystallography. From 33 selected molecules, we identified 18 new ligands and determined 13 crystal structures. Most interesting were those bound to the open cavity, where the buried site opens to bulk solvent. Here, highly unusual ligands for this cavity had been predicted, including large ligands with polar tails; these were confirmed both by binding and by crystallography. In docking, incorporating protein flexibility with thermodynamic weightings may thus access new ligand chemotypes. The MD approach to accessing and, crucially, weighting such alternative states may find general applicability.

First-Principles Calculations and Molecular Dynamics Simulations on Effect of Hydrogen Impurity in Lead Titanate Films

2016 ◽  
Author(s):  
Lin Zhu ◽  
Jeong Ho You ◽  
Jinghong Chen
Keyword(s):  
Molecular Dynamics ◽  
First Principles ◽  
Hysteresis Loops ◽  
Md Simulations ◽  
Energy Difference ◽  
Effective Hamiltonian ◽  
First Principles Calculations ◽  
Hydrogen Impurity ◽  
Penalty Term ◽  
Energy Penalty

Properties of ferroelectric films are highly influenced by inevitable defects, such as hydrogen impurity. This study is focused on theoretical and numerical studies to probe effects of hydrogen contamination on ferroelectric stability in PbTiO3 (PTO) films using the first-principles effective Hamiltonian. First-principles calculations are performed to determine the possible position, formation energy, and mobility of hydrogen impurity atom, and the calculated results are used as inputs to molecular dynamics (MD) simulations in a large system. The hydrogen atom is able to move along the polarization with small energy barriers. The energy difference between a hydrogen contaminated PTO and a pure PTO is considered as an energy penalty term induced by hydrogen contamination and has been added to the effective Hamiltonian. Then, the MD effective Hamiltonian with the energy penalty is employed in MD simulations to investigate the effects of hydrogen contamination on the ferroelectric responses of PTO films with various thicknesses and temperatures. The hysteresis loops are presented and analyzed for PTO films with various concentrations of hydrogen impurities and thicknesses. Hydrogen contamination reduces the remnant polarization, especially for thin films. As the concentration of hydrogen impurities increases, the critical thickness increases. By analyzing the vertical cross section snapshots, it has been found that the hydrogen impurity atoms near interfaces affect the polarization throughout the entire PTO films.

scholarly journals Patterns in Protein Flexibility: A Comparison of NMR “Ensembles”, MD Trajectories, and Crystallographic B-Factors

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1484
Author(s):  
Christopher Reinknecht ◽  
Anthony Riga ◽  
Jasmin Rivera ◽  
David A. Snyder
Keyword(s):  
Protein Flexibility ◽  
Molecular Machines ◽  
Md Simulations ◽  
Peptide Bond ◽  
Structure Calculation ◽  
Atomic Scale ◽  
Heavy Atoms ◽  
Structural Ensembles ◽  
Atomic Coordinates ◽  
Motional Behavior

Proteins are molecular machines requiring flexibility to function. Crystallographic B-factors and Molecular Dynamics (MD) simulations both provide insights into protein flexibility on an atomic scale. Nuclear Magnetic Resonance (NMR) lacks a universally accepted analog of the B-factor. However, a lack of convergence in atomic coordinates in an NMR-based structure calculation also suggests atomic mobility. This paper describes a pattern in the coordinate uncertainties of backbone heavy atoms in NMR-derived structural “ensembles” first noted in the development of FindCore2 (previously called Expanded FindCore: DA Snyder, J Grullon, YJ Huang, R Tejero, GT Montelione, Proteins: Structure, Function, and Bioinformatics 82 (S2), 219–230) and demonstrates that this pattern exists in coordinate variances across MD trajectories but not in crystallographic B-factors. This either suggests that MD trajectories and NMR “ensembles” capture motional behavior of peptide bond units not captured by B-factors or indicates a deficiency common to force fields used in both NMR and MD calculations.

scholarly journals Conformational Ensembles by NMR and MD Simulations in Model Heptapeptides with Select Tri-Peptide Motifs

2021 ◽  
Vol 22 (3) ◽  
pp. 1364
Author(s):  
V. V. Krishnan ◽  
Timothy Bentley ◽  
Alina Xiong ◽  
Kalyani Maitra
Keyword(s):  
Principal Component ◽  
Md Simulations ◽  
Conformational Space ◽  
Random Coil ◽  
Radius Of Gyration ◽  
Small Peptides ◽  
Conformational Ensembles ◽  
Solution State ◽  
Peptide Motifs ◽  
Explicit Solvent

Both nuclear magnetic resonance (NMR) and molecular dynamics (MD) simulations are routinely used in understanding the conformational space sampled by peptides in the solution state. To investigate the role of single-residue change in the ensemble of conformations sampled by a set of heptapeptides, AEVXEVG with X = L, F, A, or G, comprehensive NMR, and MD simulations were performed. The rationale for selecting the particular model peptides is based on the high variability in the occurrence of tri-peptide E*L between the transmembrane β-barrel (TMB) than in globular proteins. The ensemble of conformations sampled by E*L was compared between the three sets of ensembles derived from NMR spectroscopy, MD simulations with explicit solvent, and the random coil conformations. In addition to the estimation of global determinants such as the radius of gyration of a large sample of structures, the ensembles were analyzed using principal component analysis (PCA). In general, the results suggest that the -EVL- peptide indeed adopts a conformational preference that is distinctly different not only from a random distribution but also from other peptides studied here. The relatively straightforward approach presented herein could help understand the conformational preferences of small peptides in the solution state.

scholarly journals Simulation of Spectra Code (SOS) for ITER Active Beam Spectroscopy

Atoms ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 30 ◽  
Author(s):  
Manfred von Hellermann ◽  
Maarten de Bock ◽  
Oleksandr Marchuk ◽  
Detlev Reiter ◽  
Stanislav Serov ◽  
...  
Keyword(s):  
Charge Exchange ◽  
Stark Effect ◽  
Fusion Reaction ◽  
Line Emission ◽  
High Energy ◽  
Fusion Reactions ◽  
General Applicability ◽  
Generic Structure ◽  
Nuclear Fusion Reactions ◽  
Simulation Of Spectra

The concept and structure of the Simulation of Spectra (SOS) code is described starting with an introduction to the physics background of the project and the development of a simulation tool enabling the modeling of charge-exchange recombination spectroscopy (CXRS) and associated passive background spectra observed in hot fusion plasmas. The generic structure of the code implies its general applicability to any fusion device, the development is indeed based on over two decades of spectroscopic observations and validation of derived plasma data. Four main types of active spectra are addressed in SOS. The first type represents thermal low-Z impurity ions and the associated spectral background. The second type of spectra represent slowing-down high energy ions created from either thermo-nuclear fusion reactions or ions from injected high energy neutral beams. Two other modules are dedicated to CXRS spectra representing bulk plasma ions (H+, D+, or T+) and beam emission spectroscopy (BES) or Motional Stark Effect (MSE) spectrum appearing in the same spectral range. The main part of the paper describes the physics background for the underlying emission processes: active and passive CXRS emission, continuum radiation, edge line emission, halo and plume effect, or finally the charge exchange (CX) cross-section effects on line shapes. The description is summarized by modeling the fast ions emissions, e.g., either of the α particles of the fusion reaction or of the beam ions itself.

scholarly journals How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

2020 ◽  
Vol 21 (16) ◽  
pp. 5933 ◽  
Author(s):  
Mariona Torrens-Fontanals ◽  
Tomasz Maciej Stepniewski ◽  
David Aranda-García ◽  
Adrián Morales-Pastor ◽  
Brian Medel-Lacruz ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Data ◽  
Md Simulations ◽  
Full Potential ◽  
Missing Information ◽  
X Ray Crystallography ◽  
Cryo Electron Microscopy ◽  
G Protein Coupled ◽  
Gpcr Signal ◽  
Important Drug

G protein-coupled receptors (GPCRs) are implicated in nearly every physiological process in the human body and therefore represent an important drug targeting class. Advances in X-ray crystallography and cryo-electron microscopy (cryo-EM) have provided multiple static structures of GPCRs in complex with various signaling partners. However, GPCR functionality is largely determined by their flexibility and ability to transition between distinct structural conformations. Due to this dynamic nature, a static snapshot does not fully explain the complexity of GPCR signal transduction. Molecular dynamics (MD) simulations offer the opportunity to simulate the structural motions of biological processes at atomic resolution. Thus, this technique can incorporate the missing information on protein flexibility into experimentally solved structures. Here, we review the contribution of MD simulations to complement static structural data and to improve our understanding of GPCR physiology and pharmacology, as well as the challenges that still need to be overcome to reach the full potential of this technique.

Conformation and electronic structure of Carbidopa. A QM/MD study

2016 ◽  
Vol 15 (01) ◽  
pp. 1650002
Author(s):  
Ghader M. Sukker ◽  
Nuha Wazzan ◽  
Ashour Ahmed ◽  
Rifaat Hilal
Keyword(s):  
Density Functional ◽  
Minimum Energy ◽  
Geometry Optimization ◽  
Md Simulations ◽  
Energy Structure ◽  
Functional Theory ◽  
Conformational Preferences ◽  
The Density Functional Theory ◽  
Quantum Chemical Topology ◽  
Bonding Characteristics

Carbidopa (CD) is a drug used in combination with L-dopa (LD) in treatment of Parkinson’s disease (PD). CD is an inhibitor for enzyme decarboxylase, yet its mode of action is not entirely known although it is believed to involve enzyme shape recognition. The present work attempts to investigate the conformational preferences of CD. Tight geometry optimization at the density functional theory (DFT)/B3LYP/6-311[Formula: see text]G** level of theory has been carried out. The shallow nature of the potential energy surface (PES) and the presence of several local minima within a small energy range necessitate the launching of DFT-based molecular dynamics (MD) simulations. Two MD experiments were submitted for 35,000 points each. The complete trajectory in time domain of 10.5 ps is analyzed and discussed. The global minimum energy structure of CD is localized and identified by subsequent frequency calculations. The quantum theory of atom in molecules (QTAIMs) is used to extract and compare the quantum chemical topology features of the electron density distribution in CD and LD. Bonding characteristics are analyzed and discussed within the natural bond orbital (NBO) framework.

scholarly journals Markov models for the elucidation of allosteric regulation

2018 ◽  
Vol 373 (1749) ◽  
pp. 20170178 ◽  
Author(s):  
Ushnish Sengupta ◽  
Birgit Strodel
Keyword(s):  
Markov Models ◽  
Allosteric Regulation ◽  
Md Simulations ◽  
Markov Modelling ◽  
Conformational Ensembles ◽  
Markov State ◽  
Protein Allostery ◽  
Markov State Models ◽  
State Models ◽  
Allosteric Mechanisms

Allosteric regulation refers to the process where the effect of binding of a ligand at one site of a protein is transmitted to another, often distant, functional site. In recent years, it has been demonstrated that allosteric mechanisms can be understood by the conformational ensembles of a protein. Molecular dynamics (MD) simulations are often used for the study of protein allostery as they provide an atomistic view of the dynamics of a protein. However, given the wealth of detailed information hidden in MD data, one has to apply a method that allows extraction of the conformational ensembles underlying allosteric regulation from these data. Markov state models are one of the most promising methods for this purpose. We provide a short introduction to the theory of Markov state models and review their application to various examples of protein allostery studied by MD simulations. We also include a discussion of studies where Markov modelling has been employed to analyse experimental data on allosteric regulation. We conclude our review by advertising the wider application of Markov state models to elucidate allosteric mechanisms, especially since in recent years it has become straightforward to construct such models thanks to software programs like PyEMMA and MSMBuilder. This article is part of a discussion meeting issue ‘Allostery and molecular machines’.

Spreading of SARS-CoV-2 via Heating, Ventilation, and Air Conditioning Systems—An Overview of Energy Perspective and Potential Solutions

2020 ◽  
Vol 143 (8) ◽  
Author(s):  
Ahmad K. Sleiti ◽  
Samer F. Ahmed ◽  
Saud A. Ghani
Keyword(s):  
Air Conditioning ◽  
High Performance ◽  
Public Perception ◽  
High Efficiency ◽  
Uv Light ◽  
Experimental Studies ◽  
High Energy ◽  
Penalty Cost ◽  
Energy Penalty ◽  
Air Conditioning Systems

Abstract The role of heating, ventilation, and air conditioning systems (HVAC) in spreading SARS-CoV-2 is a complex topic and has not been studied thoroughly. There are some existing strategies and technologies for health and high performance buildings; however, applications to other types of buildings come at large energy penalty: cost; design, regulations and standards changes, and varied public perception. In the present work, different factors and strategies are reviewed and discussed and suggested mitigations and solutions are provided including the required air flowrates with the presence of infectors with and without mask and disinfection techniques including ultraviolet (UV) light. Experimental and numerical research in open literature suggests that the airborne transmission of SARS-CoV-2 is sufficiently likely. However, in situ detailed experimental studies are still needed to understand the different scenarios of the virus spread. Displacement ventilation, underfloor air distribution, chilled beams, radiant ceiling panels, and laminar flow systems have varied effectiveness. High-efficiency particulate arrestance (HEPA) filters and UV light can clean viruses but at high energy cost. Suggested solutions to reduce the infection probability include recommended levels of ventilation and a combination of virus sampling technologies including cyclones, liquid impinger, filters, electrostatic precipitators, and water-based condensation.

scholarly journals Insights into the origin of the high energy-conversion efficiency of F1-ATPase

2019 ◽  
Vol 116 (32) ◽  
pp. 15924-15929 ◽  
Author(s):  
Kwangho Nam ◽  
Martin Karplus
Keyword(s):  
Single Molecule ◽  
Atp Hydrolysis ◽  
Theoretical Models ◽  
Adenosine Diphosphate ◽  
Energy Conversion Efficiency ◽  
High Energy ◽  
Structural Deformation ◽  
Coupling Mechanism ◽  
Surprising Result ◽  
X Ray Crystallography

Our understanding of the rotary-coupling mechanism of F1-ATPase has been greatly enhanced in the last decade by advances in X-ray crystallography, single-molecular imaging, and theoretical models. Recently, Volkán-Kacsó and Marcus [S. Volkán-Kacsó, R. A. Marcus, Proc. Natl. Acad. Sci. U.S.A. 112, 14230 (2015)] presented an insightful thermodynamic model based on the Marcus reaction theory coupled with an elastic structural deformation term to explain the observed γ-rotation angle dependence of the adenosine triphosphate (ATP)/adenosine diphosphate (ADP) exchange rates of F1-ATPase. Although the model is successful in correlating single-molecule data, it is not in agreement with the available theoretical results. We describe a revision of the model, which leads to consistency with the simulation results and other experimental data on the F1-ATPase rotor compliance. Although the free energy liberated on ATP hydrolysis by F1-ATPase is rapidly dissipated as heat and so cannot contribute directly to the rotation, we show how, nevertheless, F1-ATPase functions near the maximum possible efficiency. This surprising result is a consequence of the differential binding of ATP and its hydrolysis products ADP and Pi along a well-defined pathway.

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