Abstract

Cavitation bubble collapse near rough solid wall is modeled by the multi- relaxation-time (MRT) pseudopotential lattice Boltzmann (LB) model. The modified forcing scheme, which can achieve LB model’s thermodynamic consistency by tuning a parameter related with the particle interaction range, is adopted to achieve desired stability and density ratio. The bubble collapse near rough solid wall was simulated by the improved MRT pseudopotential LB model. The mechanism of bubble collapse is studied by investigating the bubble profiles, pressure field and velocity field evolution. The eroding effects of collapsing bubble are analyzed in details. It is found that the process and the effect of the interaction between bubble collapse and rough solid wall are affected seriously by the geometry of solid boundary. At the same time, it demonstrates that the MRT pseudopotential LB model is a potential tool for the investigation of the interaction mechanism between the collapsing bubble and complex geometry boundary Modeling for a Chemogenomics-Driven NCR, Lfpep, Brevinin-1Sa and kaliocin-1 peptidomimetic Drug Discovery Neo-agent Collapsing Cavitation Bubble near Rough Solid Wall by Mulit-Relaxation-Time Pseudopotential Lattice Boltzmann Model against Candida albicans antimicrobial CXG motif signatures.

Keywords

Modeling for Collapsing; Cavitation Bubble; Rough Solid Wall; Mulit-Relaxation-Time; Pseudopotential Lattice; Boltzmann Model; Chemogenomics-Driven; NCR, Lfpep, Brevinin-1Sa kaliocin-1 peptidomimetic; Drug Discovery; Neo-agent; Candida albicans; antimicrobial CXG motif signatures, Cavitation Bubble, Bubble Collapse, Lattice Boltzmann Method, Pseudopotential Model, Rough Solid Wall;

Abstract

Background

Molecular Mechanics (MM) is the method of choice for computational studies of biomolecular systems owing to its modest computational cost, which makes it possible to routinely perform molecular dynamics (MD) simulations on chemical systems of biophysical and biomedical relevance.

Scope of Review

As one of the main factors limiting the accuracy of MD results is the empirical force field used, the present paper offers a review of recent developments in the CHARMM additive force field, one of the most popular bimolecular force fields. Additionally, we present a detailed discussion of the CHARMM Drude polarizable force field, anticipating a growth in the importance and utilization of polarizable force fields in the near future. Throughout the discussion emphasis is placed on the force fields’ parametrization philosophy and methodology.

Major Conclusions

Recent improvements in the CHARMM additive force field are mostly related to newly found weaknesses in the previous generation of additive force fields. Beyond the additive approximation is the newly available CHARMM Drude polarizable force field, which allows for MD simulations of up to 1 microsecond on proteins, DNA, lipids and carbohydrates.

General Significance

Addressing the limitations ensures the reliability of the new CHARMM36 additive force field for the types of calculations that are presently coming into routine computational reach while the availability of the Drude polarizable force fields offers a model that is an inherently more accurate model of the underlying physical forces driving CHARMM additive and polarizable force fields for biophysics and computer-aided drug design as a Chemogenomics-Driven NCR, Lfpep, Brevinin-1Sa and kaliocin-1 peptidomimetic Drug Discovery Neo-agent against Candida albicans antimicrobial CXG motif structures and dynamics signatures.

Keywords

CHARMM additives, polarizable force fields, biophysics; computer-aided drug design; Chemogenomics-Driven; NCR, Lfpep, Brevinin-1Sa kaliocin-1; peptidomimetic; Drug Discovery; Neo-agent; Candida albicans; antimicrobial; CXG motif signatures;molecular dynamics, empirical force field, potential energy function, molecular mechanics, computer-aided drug design, biophysics

Abstract

Next-generation molecular force fields deliver accurate descriptions of non-covalent interactions by employing more elaborate functional forms than their predecessors. Much work has been dedicated to improving the description of the electrostatic potential (ESP) generated by these force fields. A common approach to improving the ESP is by augmenting the point charges on each center with higher-order multipole moments. The resulting anisotropy greatly improves the directionality of the non-covalent bonding, with a concomitant increase in computational cost. In this work, we develop an efficient strategy for enumerating multipole interactions, by casting an efficient spherical harmonic based approach within a particle mesh Ewald (PME) framework. Although the derivation involves lengthy algebra, the final expressions are relatively compact, yielding an approach that can efficiently handle both finite and periodic systems without imposing any approximations beyond PME. Forces and torques are readily obtained, making our method well suited to modern molecular dynamics simulations.An efficient algorithm for multipole energies and derivatives based on spherical harmonics and extensions to particle mesh Ewald. Pathogenic microbes can recruit to their cell surface human proteins that are components of important proteolytic cascades involved in coagulation, fibrinolysis and innate immune response. Once located at the bacterial or fungal surface, such deployed proteins might be utilized by pathogens to facilitate invasion and dissemination within the host organism by interfering with functionality of these systems or by exploiting specific activity of the bound enzymes. After confirming ability of the fungal surface-exposed proteins to bind HPG and HK, four of them – two agglutinin-like sequence (Als) proteins CPAR2_404780 and CPAR2_404800, a heat shock protein Ssa2 and a moonlighting protein 6-phosphogluconate dehydrogenase 1 – were purified using ion-exchange chromatography, gel filtration and chromatofocusing. Then, their affinities to HPG and HK were characterized with surface plasmon resonance measurements. The determined dissociation constants for the investigated protein-protein complexes were within a 10-7 M order for the HPG binding and in a range of 10-8-10-9 M for the HK binding. Detailed characterization of adsorption of these two important plasma proteins on the fungal cell surface may help to increase our understanding of molecular mechanisms of C. parapsilosis-dependent candidiasis. Pathogenic microbes can recruit to their cell surface human proteins that are components of important proteolytic cascades involved in coagulation, fibrinolysis and innate immune response. Once located at the bacterial or fungal surface, such deployed proteins might be utilized by pathogens to facilitate invasion and dissemination within the host organism by interfering with functionality of these systems or by exploiting specific activity of the bound enzymes. Aim of the study presented here was to characterize this phenomenon in Candida parapsilosis (Ashford) Langeron et Talice – an important causative agent of systemic fungal infections (candidiases and candidemias) in humans. We have investigated the interactions of fungal surface-exposed proteins with plasminogen (HPG) and high-molecular-mass kininogen (HK) – the crucial components of human fibrinolytic system and proinflammatory/procoagulant contact-activated kinin-forming system, respectively. After confirming ability of the fungal surface-exposed proteins to bind HPG and HK, four of them – two agglutinin-like sequence (Als) proteins CPAR2_404780 and CPAR2_404800, a heat shock protein Ssa2 and a moonlighting protein 6-phosphogluconate dehydrogenase 1 – were purified using ion-exchange chromatography, gel filtration and chromatofocusing. Then, their affinities to HPG and HK were characterized with surface plasmon resonance measurements. The determined dissociation constants for the investigated protein-protein complexes were within a 10-7 M order for the HPG binding and in a range of 10-8-10-9 M for the HK binding. Detailed characterization of adsorption of these two important plasma proteins on the fungal cell surface may help to increase our understanding of molecular mechanisms of C. parapsilosis-dependent candidiasis.Abstract: Candida albicans is one of the most common opportunistic human fungal pathogens. In healthy human populations, it is a member of the normal flora of the skin, genital, and intestinal mucosa. However, C. albicansas well as other Candida species (e.g., C. parapsilosis or C. krusei) may lead to morbidity and mortality in immunocompromised patients as a consequence of fungal overgrowth and severe cutaneous or systemic infections. For the treatment of invasive candidiasis, amphotericin B-based preparations, azoles, and echinocandins are used. In the therapy of mucocutaneous infections (e.g., vaginal infections), azoles are the dominant agents. The synthetic peptides TKCFQWQRNMRKVRGPPVSCIKR Lfpep and FFSASCVPGADKGQFPNLCRLCAGTGENKCA kaliocin-1 include the sequences from positions 18 to 40 and 153 to 183 of human lactoferrin, respectively. In this research we will give the lead in a new drug discovery paradigm that focuses on mechanisms of action. Furthermore, the technologies developed in this project will offer new pharmaceutical chemico-scaffolds to facilitate basic scientific research. Within the next three years, Biogenea SA will contribute proprietary resources to take the new drug compounds through clinical trials and ultimately to market using an efficient algorithm for multipole energies and derivatives based on spherical harmonics and extensions to particle mesh Ewald Binding of human plasminogen and high-molecular-mass kininogen by cell surface-exposed proteins of Candida parapsilosis.

Keywords

Ultimate; target-ligand based approaches;experimental; predicted binding affinity; matrices; Chemogenomics-Driven; NCR, Lfpep, Brevinin-1Sa;kaliocin-1; peptidomimetic; Drug Discovery; Neo-agent; Candida albicans; CXG motif; signatures; efficient algorithm; multipole energies; derivatives; spherical harmonics; extensions; particle mesh Ewald;

Abstract

Next-generation molecular force fields deliver accurate descriptions of non-covalent interactions by employing more elaborate functional forms than their predecessors. Much work has been dedicated to improving the description of the electrostatic potential (ESP) generated by these force fields. A common approach to improving the ESP is by augmenting the point charges on each center with higher-order multipole moments. The resulting anisotropy greatly improves the directionality of the non-covalent bonding, with a concomitant increase in computational cost. In this work, we develop an efficient strategy for enumerating multipole interactions, by casting an efficient spherical harmonic based approach within a particle mesh Ewald (PME) framework. Although the derivation involves lengthy algebra, the final expressions are relatively compact, yielding an approach that can efficiently handle both finite and periodic systems without imposing any approximations beyond PME. Forces and torques are readily obtained, making our method well suited to modern molecular dynamics simulations. There is evidence that the α-synucleinopathies Parkinson’s disease (PD) and the Parkinson variant of multiple system atrophy (MSA-P) overlap at multiple levels. Both disorders are characterized by deposition of abnormally phosphorylated fibrillar α-synuclein within the central nervous system suggesting shared pathophysiological mechanisms. Currently, there is no disease-modifying treatment for MSA. In other senses, it has been previously shown that next-generation active vaccination technology with short peptides, AFFITOPEs®, was effective in two transgenic models of synucleinopathies at reducing behavioral deficits, α-syn accumulation and inflammation. We demonstrate here for the first time an efficient emerging template for drug discovery algorithm for multipole energies and derivatives based on spherical harmonics and extensions to particle α-Synuclein aggregation simulated mesh Ewalds on Amyloid β-sheet helix-rich Val-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr peptide mimic modulators in α-synucleinopathy interfering amyloidogenesis pathways.

Keywords

Aggregation simulated studies;Amyloid β-sheet; helix-richpeptide; mimic modulators;α-Synuclein; aggregation;emerging templated;rug discovery;α-synucleinopathies;interfering amyloidogenesis pathways; Val-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr; multipole energies; spherical harmonics; extensions; particle mesh Ewald;

Abstract

It is well known that quantum computers are superior to classical computers in efficiently simulating quantum systems. The occurrence of quantum tunneling through a barrier, together with the oscillation of the state in potential wells, are clearly observed through the experimental results. This experiment has clearly demonstrated the possibility to observe and study profound physical phenomena within even the reach of small quantum computers. Quantum simulation is one of the most important aims of quantum computation ever since Feynman studied the likelihood of simulating one quantum system by another1. Recent years have witnessed fruitful results in the development of quantum computation, and it has been demonstrated that quantum computers can solve certain types of problems with a level of efficiency beyond the capability of classical computers2,3,4,5,6, among which the simulation of the dynamics of quantum systems is especially attractive because of the exponential improvement in computational resources and speeds. Quantum simulation has become a subject of intense investigation and has been realized in various situations, such as system evolution with a many-body interaction Hamiltonian7,8,9,10, the dynamics of entanglement11,12, quantum phase transitions13,14, and calculations of molecular properties15,16,17,18,19. Quantum tunneling plays an essential role in many quantum phenomena, such as the tunneling of superconducting Cooper pairs20 and alpha decay21. Moreover, tunneling has been widely applied in modern devices and modern experimental techniques, such as the tunnel diode22, the scanning tunneling microscope23 and so on. As a unique fundamental concept in quantum mechanics, the simulation of quantum tunneling is of great significance. Many important science problems, such as lattice quantum chromodynamics24, can be dealt with similarly. However due to the large number of quantum gates and qubits required, the simulation of quantum tunneling in a quantum computer has remained untested experimentally. Recently Sornborger25 proposed a digital simulation algorithm for demonstrating the tunneling of a particle in a double-well potential with no ancillary qubits, and at least halved the number of quantum gates. This makes it possible to simulate this important quantum effect in today’s quantum information processors with only a few qubits. Here we report the first experimental simulation of quantum tunneling through potential barriers, a widespread phenomenon of a unique quantum nature, via NMR techniques. Our experiment is based on a digital particle simulation algorithm and requires very few spin-1/2 nuclei without the need of ancillary qubits.In this paper, we report the first experimental digital quantum simulation of this significant quantum phenomenon via a liquid nuclear magnetic resonance (NMR) quantum information processor. In the experiment, the continuous process of one-dimensional tunneling of a particle through a potential barrier is clearly demonstrated, and the oscillation of the particle in potential wells is clearly observed. Our experiment has shown that with very few qubits, interesting quantum effects such as tunneling dynamics can be simulated with techniques which are within reach of current experimental simulation of quantum tunneling in small α-Synuclein aggregation simulated systems on Amyloid β-sheet helix-rich Val-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr peptide mimic modulators in α-synucleinopathy interfering amyloidogenesis quantum architectured pathways.

Keywords

Experimental simulation; quantum tunneling; small; α-Synuclein aggregation; simulated systems; Amyloid β-sheet; helix-rich; Val-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr; peptide mimic modulators; α-synucleinopathy; interfering; amyloidogenesis pathways;

Abstract

Recently, it is shown that there is a crucial contradiction within von Neumann’s theory [K. Nagata and T. Nakamura, Int. J. Theor. Phys. 49, 162 (2010)]. We derive a proposition concerning a quantum expected value under the assumption of the existence of the directions in a spin-1/2 system. The quantum predictions within the formalism of von Neumann’s projective measurement cannot coexist with the proposition concerning the existence of the directions. Therefore, we have to give up either the existence of the directions or the formalism of von Neumann’s projective measurement. Hence, there is a crucial contradiction within von Neumann’s theory. We discuss that this crucial contradiction makes the theoretical formulation of Deutsch’s algorithm questionable. Especially, we systematically describe our assertion based on more mathematical analysis using raw data. Our discussion, here, improves previously published argumentations very much whether Von Neumann’s Theory Meet al-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr peptide mimic modulators in α-synucleinopathy interfering amyloidogenesis Quantum Computated pathways.

Keywords

Von Neumann’s Theory; Meet; al-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr; peptide mimic; modulators; α-synucleinopathy; interfering amyloidogenesis; Quantum Computated; pathways; Quantum Measurement Theory, Quantum Computer, Formalism;Subject Areas; Applied Physics;

Abstract

Cavitation bubble collapse near rough solid wall is modeled by the multi- relaxation-time (MRT) pseudopotential lattice Boltzmann (LB) model. The modified forcing scheme, which can achieve LB model’s thermodynamic consistency by tuning a parameter related with the particle interaction range, is adopted to achieve desired stability and density ratio. The bubble collapse near rough solid wall was simulated by the improved MRT pseudopotential LB model. The mechanism of bubble collapse is studied by investigating the bubble profiles, pressure field and velocity field evolution. The eroding effects of collapsing bubble are analyzed in details. It is found that the process and the effect of the interaction between bubble collapse and rough solid wall are affected seriously by the geometry of solid boundary. At the same time, it demonstrates that the MRT pseudopotential LB model is a potential tool for the investigation of the interaction mechanism between the collapsing bubble and complex geometry Modeling boundaries for Collapsing al-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr peptide mimic modulators in α-synucleinopathy interfering amyloidogenesis Cavitations Bubble near Rough Solid Wall by Mulit-Relaxation-Time Pseudopotential Lattice Boltzmann Quantum Computated α-Synuclein aggregation simulated Model.

Keywords

Modeling for Collapsing; al-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr peptide mimic; modulators; α-synucleinopathy; interfering amyloidogenesis; Cavitations; Bubble; Rough; Solid Wall; Mulit-Relaxation-Time; Pseudopotential; Lattice Boltzmann; Quantum Computated; α-Synuclein; aggregation; simulated Model;

Abstract

There is evidence that the α-synucleinopathies Parkinson’s disease (PD) and the Parkinson variant of multiple system atrophy (MSA-P) overlap at multiple levels. Both disorders are characterized by deposition of abnormally phosphorylated fibrillar α-synuclein within the central nervous system suggesting shared pathophysiological mechanisms. Currently, there is no disease-modifying treatment for MSA. In other senses, it has been previously shown that next-generation active vaccination technology with short peptides, AFFITOPEs®, was effective in two transgenic models of synucleinopathies at reducing behavioral deficits, α-syn accumulation and inflammation. We demonstrate here for the first time a drug discovery platform for the generation of analogues of the heptapeptide H-Arg-Lys-Val-MePhe-Tyr-Thr-Trp- OH2, an novel multitargeted inhibitors of Aβ-peptide aggregation, to cross-react with α-synuclein interfering with its fibril formation through novel efficient algorithms for multipole energies and derivatives based on spherical harmonics and extensions to Aggregation simulated studies on Amyloid β-sheet helix-rich Val-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr peptide mimic modulators of α-Synuclein aggregation as a emerging template for drug discovery in α-synucleinopathy interfering amyloidogenesis particle mesh Ewald pathways.

Keywords

Aggregation simulated studiesAmyloid β-sheet helix-richpeptide mimic modulators
α-Synuclein aggregationemerging templatedrug discoveryα-synucleinopathiesinterfering amyloidogenesis pathways

Abstract

There is evidence that the α-synucleinopathies Parkinson’s disease (PD) and the Parkinson variant of multiple system atrophy (MSA-P) overlap at multiple levels. Both disorders are characterized by deposition of abnormally phosphorylated fibrillar α-synuclein within the central nervous system suggesting shared pathophysiological mechanisms. Currently, there is no disease-modifying treatment for MSA. In other senses, it has been previously shown that next-generation active vaccination technology with short peptides, AFFITOPEs®, was effective in two transgenic models of synucleinopathies at reducing behavioral deficits, α-syn accumulation and inflammation. We demonstrate here for the first time a drug discovery platform for the generation of analogues of the heptapeptide H-Arg-Lys-Val-MePhe-Tyr-Thr-Trp- OH2, an novel multitargeted inhibitors of Aβ-peptide aggregation, to cross-react with α-synuclein interfering with its fibril formation through novel efficient algorithms for multipole energies and derivatives based on spherical harmonics and extensions to Aggregation simulated studies on Amyloid β-sheet helix-rich Val-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr peptide mimic modulators of α-Synuclein aggregation as a emerging template for drug discovery in α-synucleinopathy interfering amyloidogenesis particle mesh Ewald pathways.

Keywords

Aggregation simulated studiesAmyloid β-sheet helix-richpeptide mimic modulators
α-Synuclein aggregationemerging templatedrug discoveryα-synucleinopathiesinterfering amyloidogenesis pathways

Abstract

Next-generation molecular force fields deliver accurate descriptions of non-covalent interactions by employing more elaborate functional forms than their predecessors. Much work has been dedicated to improving the description of the electrostatic potential (ESP) generated by these force fields. A common approach to improving the ESP is by augmenting the point charges on each center with higher-order multipole moments. The resulting anisotropy greatly improves the directionality of the non-covalent bonding, with a concomitant increase in computational cost. In this work, we develop an efficient strategy for enumerating multipole interactions, by casting an efficient spherical harmonic based approach within a particle mesh Ewald (PME) framework. Although the derivation involves lengthy algebra, the final expressions are relatively compact, yielding an approach that can efficiently handle both finite and periodic systems without imposing any approximations beyond PME. Forces and torques are readily obtained, making our method well suited to modern molecular dynamics simulations.Aggregation simulated studies on Ewald Aggregation simulated studies on an efficient algorithm for multipole energies and derivatives based on spherical harmonics and extensions to particle mesh Amyloid β-sheet helix-rich Val-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr peptide mimic modulators of α-Synuclein aggregation as a emerging template for drug discovery in α-synucleinopathy interfering amyloidogenesis pathways.

Keywords

Ewald Aggregation, simulated studies, algorithm, multipole energies, spherical harmonics, extensions; particle mesh; Amyloid β-sheet helix-rich; Val-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr peptide mimic; modulators; α-Synuclein aggregation; emerging template; drug discovery; α-synucleinopathy; interfering amyloidogenesis pathways;