scholarly journals Atomic-scale Characterization of Mature HIV-1 Capsid Stabilization by Inositol Hexakisphosphate (IP6)

2020 ◽  
Author(s):  
Alvin Yu ◽  
Elizabeth M.Y. Lee ◽  
Jaehyeok Jin ◽  
Gregory A. Voth
Keyword(s):  
Kinetic Studies ◽  
Binding Pocket ◽  
Free Energy Calculations ◽  
Atomic Scale ◽  
Binding Modes ◽  
Ligand Density ◽  
Immunodeficiency Virus ◽  
Scale Characterization ◽  
Dynamics Simulations

AbstractInositol hexakisphosphates (IP6) are cellular cofactors that promote the assembly of mature capsids of the human immunodeficiency virus (HIV). These negatively charged molecules coordinate an electropositive ring of arginines at the center of pores distributed throughout the capsid surface. Kinetic studies indicate that the binding of IP6 increases the stable life times of the capsid by several orders of magnitude from minutes to hours. Using all-atom molecular dynamics simulations, we uncover the mechanisms that underlie the unusually high stability of mature capsids in complex with IP6. We find that capsid hexamers and pentamers have differential binding modes for IP6. Ligand density calculations show three sites of interaction with IP6 including at a known capsid-inhibitor binding pocket. Free energy calculations demonstrate that IP6 preferentially stabilizes pentamers over hexamers to enhance fullerene modes of assembly. These results elucidate the molecular role of IP6 in stabilizing and assembling the retroviral capsid.

scholarly journals Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP6)

2020 ◽  
Vol 6 (38) ◽  
pp. eabc6465 ◽  
Author(s):  
Alvin Yu ◽  
Elizabeth M. Y. Lee ◽  
Jaehyeok Jin ◽  
Gregory A. Voth
Keyword(s):  
Kinetic Studies ◽  
Binding Pocket ◽  
Free Energy Calculations ◽  
Atomic Scale ◽  
Binding Modes ◽  
Ligand Density ◽  
Scale Characterization ◽  
Dynamics Simulations

Inositol hexakisphosphates (IP6) are cellular cofactors that promote the assembly of mature capsids of HIV. These negatively charged molecules coordinate an electropositive ring of arginines at the center of pores distributed throughout the capsid surface. Kinetic studies indicate that the binding of IP6 increases the stable lifetimes of the capsid by several orders of magnitude from minutes to hours. Using all-atom molecular dynamics simulations, we uncover the mechanisms that underlie the unusually high stability of mature capsids in complex with IP6. We find that capsid hexamers and pentamers have differential binding modes for IP6. Ligand density calculations show three sites of interaction with IP6 including at a known capsid inhibitor binding pocket. Free energy calculations demonstrate that IP6 preferentially stabilizes pentamers over hexamers to enhance fullerene modes of assembly. These results elucidate the molecular role of IP6 in stabilizing and assembling the retroviral capsid.

scholarly journals Computational Perspectives into Plasmepsins Structure—Function Relationship: Implications to Inhibitors Design

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Alejandro Gil L. ◽  
Pedro A. Valiente ◽  
Pedro G. Pascutti ◽  
Tirso Pons
Keyword(s):  
Structure Function ◽  
Free Energy Calculations ◽  
Special Focus ◽  
Binding Modes ◽  
Linear Interaction ◽  
Lead Compounds ◽  
Structure Function Relationship ◽  
Function Relationship ◽  
Dynamics Simulations ◽  
Selection Of

The development of efficient and selective antimalariais remains a challenge for the pharmaceutical industry. The aspartic proteases plasmepsins, whose inhibition leads to parasite death, are classified as targets for the design of potent drugs. Combinatorial synthesis is currently being used to generate inhibitor libraries for these enzymes, and together with computational methodologies have been demonstrated capable for the selection of lead compounds. The high structural flexibility of plasmepsins, revealed by their X-ray structures and molecular dynamics simulations, made even more complicated the prediction of putative binding modes, and therefore, the use of common computational tools, like docking and free-energy calculations. In this review, we revised the computational strategies utilized so far, for the structure-function relationship studies concerning the plasmepsin family, with special focus on the recent advances in the improvement of the linear interaction estimation (LIE) method, which is one of the most successful methodologies in the evaluation of plasmepsin-inhibitor binding affinity.

The Role of SiH3 Diffusion in Determining the Surface Smoothness of Plasma-Deposited Amorphous Si Thin Films: An Atomic-Scale Analysis

2005 ◽  
Vol 862 ◽  
Author(s):  
Mayur S. Valipa ◽  
Tamas Bakos ◽  
Eray S. Aydil ◽  
Dimitrios Maroudas
Keyword(s):  
Thin Films ◽  
Density Functional ◽  
Activation Barrier ◽  
Density Functional Theory Calculations ◽  
Atomic Scale ◽  
Functional Theory ◽  
Weak Adsorption ◽  
Dynamics Simulations ◽  
Hydrogenated Amorphous

AbstractDevice-quality hydrogenated amorphous silicon (a-Si:H) thin films grown under conditions where the SiH3 radical is the dominant deposition precursor are remarkably smooth, as the SiH3 radical is very mobile and fills surface valleys during its diffusion on the a-Si:H surface. In this paper, we analyze atomic-scale mechanisms of SiH3 diffusion on a-Si:H surfaces based on molecular-dynamics simulations of SiH3 radical impingement on surfaces of a-Si:H films. The computed average activation barrier for radical diffusion on a-Si:H is 0.16 eV. This low barrier is due to the weak adsorption of the radical onto the a-Si:H surface and its migration predominantly through overcoordination defects; this is consistent with our density functional theory calculations on crystalline Si surfaces. The diffusing SiH3 radical incorporates preferentially into valleys on the a-Si:H surface when it transfers an H atom and forms a Si-Si backbond, even in the absence of dangling bonds.

Texture of nanocrystalline solids: atomic scale characterization and applications

2018 ◽  
Vol 51 (1) ◽  
pp. 124-132 ◽  
Author(s):  
J. C. E ◽  
Y. Cai ◽  
Z. Y. Zhong ◽  
M. X. Tang ◽  
X. R. Zhu ◽  
...  
Keyword(s):  
Shock Wave ◽  
Pole Figure ◽  
Inverse Pole Figure ◽  
Orientation Distribution ◽  
Fiber Texture ◽  
Atomic Scale ◽  
X Ray Diffraction ◽  
Wave Compression ◽  
Scale Characterization ◽  
Dynamics Simulations

A methodology is presented to characterize the crystallographic texture of atomic configurations on the basis of Euler angles. Texture information characterized by orientation map, orientation distribution function, texture index, pole figure and inverse pole figure is obtained. The paper reports the construction and characterization of the texture of nanocrystalline configurations with different grain numbers, grain sizes and percentages of preferred orientation. The minimum grain number for texture-free configurations is ∼2500. The effect of texture on deducing grain size from simulated X-ray diffraction curves is also explored as an application case of texture analysis. In addition, molecular dynamics simulations are performed on initially texture-free nanocrystalline Ta under shock-wave loading, which shows a 〈001〉 + 〈111〉 double fiber texture after shock-wave compression.

scholarly journals Role of RNA Guanine Quadruplexes in Favoring the Dimerization of SARS Unique Domain in Coronaviruses

2020 ◽  
Author(s):  
Cécilia Hognon ◽  
Tom Miclot ◽  
Cristina Garcia Iriepa ◽  
Antonio Francés-Monerris ◽  
Stephanie Grandemange ◽  
...  
Keyword(s):  
Rational Design ◽  
Economic Consequences ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Present Contribution ◽  
Global Pandemic ◽  
Protein Dimer ◽  
Dynamics Simulations ◽  
Unique Domain

ABSTRACTCoronaviruses may produce severe acute respiratory syndrome (SARS). As a matter of fact, a new SARS-type virus, SARS-CoV-2, is responsible of a global pandemic in 2020 with unprecedented sanitary and economic consequences for most countries. In the present contribution we study, by all-atom equilibrium and enhanced sampling molecular dynamics simulations, the interaction between the SARS Unique Domain and RNA guanine quadruplexes, a process involved in eluding the defensive response of the host thus favoring viral infection of human cells. Our results evidence two stable binding modes involving an interaction site spanning either the protein dimer interface or only one monomer. The free energy profile unequivocally points to the dimer mode as the thermodynamically favored one. The effect of these binding modes in stabilizing the protein dimer was also assessed, being related to its biological role in assisting SARS viruses to bypass the host protective response. This work also constitutes a first step of the possible rational design of efficient therapeutic agents aiming at perturbing the interaction between SARS Unique Domain and guanine quadruplexes, hence enhancing the host defenses against the virus.TOC GRAPHICS

scholarly journals Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States

2020 ◽  
Author(s):  
Gustavo Cárdenas ◽  
Juan J. Nogueira
Keyword(s):  
Oxidative Stress ◽  
Charge Transfer ◽  
Excited States ◽  
Transition Density ◽  
Binding Pocket ◽  
Total Density ◽  
Binding Modes ◽  
Electronically Excited States ◽  
Electronically Excited ◽  
Dynamics Simulations

The design of more efficient photosensitizers is a matter of great importance in the field of cancer treatment by means of photodynamic therapy. One of the main processes involved in the activation of apoptosis in cancer cells is the oxidative stress on DNA once a photosensitizer is excited by light. As a consequence, it is a matter of great relevance to investigate in detail the binding modes of the chromophore with DNA, and the nature of the electronically excited states that participate in the induction of DNA damage, for example, charge-transfer states. In this work, we investigate the electronic structure of the anthraquinone photosensitizer intercalated into a double-stranded poly(dG-dC) decamer model of DNA. First, the different geometric configurations are analyzed by means of classical molecular dynamics simulations. Then, the excited states for the most relevant poses of anthraquinone inside the binding pocket are computed by an electrostatic-embedding quantum mechanics/molecular mechanics approach, where anthraquinone and one of the nearby guanine residues are described quantum mechanically to take into account intermolecular charge-transfer states. The excited states are characterized as monomer, exciton, excimer and charge-transfer states based on the analysis of the transition density matrix, and each of these contributions to the total density of states and absorption spectrum is discussed in terms of the stacking interactions. These results are relevant as they represent the footing for future studies on the reactivity of anthraquinone derivatives with DNA and give insights on possible geometrical configurations that potentially favor the oxidative stress of DNA.

Binding modes of thioflavin T and Congo red to the fibril structure of amyloid-β(1–42)

2020 ◽  
Vol 56 (55) ◽  
pp. 7589-7592 ◽  
Author(s):  
Benedikt Frieg ◽  
Lothar Gremer ◽  
Henrike Heise ◽  
Dieter Willbold ◽  
Holger Gohlke
Keyword(s):  
Congo Red ◽  
Fluorescent Dyes ◽  
Binding Free Energy ◽  
Amyloid Β ◽  
Free Energy Calculations ◽  
Thioflavin T ◽  
Binding Modes ◽  
Fibril Structure ◽  
Binding Free Energy Calculations ◽  
Dynamics Simulations

Binding modes for the amyloid-β(1–42) fibril fluorescent dyes thioflavin T and Congo red were predicted by molecular dynamics simulations and binding free energy calculations.

scholarly journals Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5927
Author(s):  
Gustavo Cárdenas ◽  
Juan J. Nogueira
Keyword(s):  
Oxidative Stress ◽  
Charge Transfer ◽  
Excited States ◽  
Transition Density ◽  
Binding Pocket ◽  
Total Density ◽  
Binding Modes ◽  
Electronically Excited States ◽  
Electronically Excited ◽  
Dynamics Simulations

The design of more efficient photosensitizers is a matter of great importance in the field of cancer treatment by means of photodynamic therapy. One of the main processes involved in the activation of apoptosis in cancer cells is the oxidative stress on DNA once a photosensitizer is excited by light. As a consequence, it is very relevant to investigate in detail the binding modes of the chromophore with DNA, and the nature of the electronically excited states that participate in the induction of DNA damage, for example, charge-transfer states. In this work, we investigate the electronic structure of the anthraquinone photosensitizer intercalated into a double-stranded poly(dG-dC) decamer model of DNA. First, the different geometric configurations are analyzed by means of classical molecular dynamics simulations. Then, the excited states for the most relevant poses of anthraquinone inside the binding pocket are computed by an electrostatic-embedding quantum mechanics/molecular mechanics approach, where anthraquinone and one of the nearby guanine residues are described quantum mechanically to take into account intermolecular charge-transfer states. The excited states are characterized as monomer, exciton, excimer, and charge-transfer states based on the analysis of the transition density matrix, and each of these contributions to the total density of states and absorption spectrum is discussed in terms of the stacking interactions. These results are relevant as they represent the footing for future studies on the reactivity of anthraquinone derivatives with DNA and give insights on possible geometrical configurations that potentially favor the oxidative stress of DNA.

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