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1.
Phys Rev E ; 104(5-1): 054408, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34942780

RESUMO

The elucidation of fundamental mechanisms underlying ion-induced radiation damage of biological systems is crucial for advancing radiotherapy with ion beams and for radiation protection in space. The study of ion-induced biodamage using the phenomenon-based multiscale approach (MSA) to the physics of radiation damage with ions has led to the prediction of nanoscale shock waves created by ions in a biological medium at the high linear energy transfer (LET). The high-LET regime corresponds to the keV and higher-energy losses by ions per nanometer, which is typical for ions heavier than carbon at the Bragg peak region in biological media. This paper reveals that the thermomechanical stress of the DNA molecule caused by the ion-induced shock wave becomes the dominant mechanism of complex DNA damage at the high-LET ion irradiation. Damage of the DNA molecule in water caused by a projectile-ion-induced shock wave is studied by means of reactive molecular dynamics simulations. Five projectile ions (carbon, oxygen, silicon, argon, and iron) at the Bragg peak energies are considered. For the chosen segment of the DNA molecule and the collision geometry, the number of DNA strand breaks is evaluated for each projectile ion as a function of the bond dissociation energy and the distance from the ion's path to the DNA strands. Simulations reveal that argon and especially iron ions induce the breakage of multiple bonds in a DNA double convolution containing 20 DNA base pairs. The DNA damage produced in segments of such size leads to complex irreparable lesions in a cell. This makes the shock-wave-induced thermomechanical stress the dominant mechanism of complex DNA damage at the high-LET ion irradiation. A detailed theory for evaluating the DNA damage caused by ions at high-LET is formulated and integrated into the MSA formalism. The theoretical analysis reveals that a single ion hitting a cell nucleus at high-LET is sufficient to produce highly complex, lethal damages to a cell by the shock-wave-induced thermomechanical stress. Accounting for the shock-wave-induced thermomechanical mechanism of DNA damage provides an explanation for the "overkill" effect observed experimentally in the dependence of cell survival probabilities on the radiation dose delivered with iron ions. This important observation provides strong experimental evidence of the ion-induced shock-wave effect and the related mechanism of radiation damage in cells.


Assuntos
Dano ao DNA , Transferência Linear de Energia , DNA , Reparo do DNA , Íons
2.
J R Soc Interface ; 18(184): 20210601, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34753309

RESUMO

The biophysical mechanism of the magnetic compass sensor in migratory songbirds is thought to involve photo-induced radical pairs formed in cryptochrome (Cry) flavoproteins located in photoreceptor cells in the eyes. In Cry4a-the most likely of the six known avian Crys to have a magnetic sensing function-four radical pair states are formed sequentially by the stepwise transfer of an electron along a chain of four tryptophan residues to the photo-excited flavin. In purified Cry4a from the migratory European robin, the third of these flavin-tryptophan radical pairs is more magnetically sensitive than the fourth, consistent with the smaller separation of the radicals in the former. Here, we explore the idea that these two radical pair states of Cry4a could exist in rapid dynamic equilibrium such that the key magnetic and kinetic properties are weighted averages. Spin dynamics simulations suggest that the third radical pair is largely responsible for magnetic sensing while the fourth may be better placed to initiate magnetic signalling particularly if the terminal tryptophan radical can be reduced by a nearby tyrosine. Such an arrangement could have allowed independent optimization of the essential sensing and signalling functions of the protein. It might also rationalize why avian Cry4a has four tryptophans while Crys from plants have only three.

3.
J Phys Chem B ; 125(34): 9652-9659, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34327996

RESUMO

A widespread hypothesis ascribes the ability of migratory birds to navigate over large distances to an inclination compass realized by the protein cryptochrome in the birds' retinae. Cryptochromes are activated by blue light, which induces a radical pair state, the spin dynamics of which may become sensitive to earth's weak magnetic fields. The magnetic information is encoded and passed on to downstream processes by structural rearrangements of the protein, the details of which remain vague. We utilize extensive all-atom molecular dynamics simulations to probe the conformational changes of pigeon cryptochrome 4 upon light activation. The structural dynamics are analyzed based on principal component analysis and with the help of distance matrices, which reveal significant changes in selected inter-residue distances. The results are evaluated and discussed with reference to the protein structure and its putative function as a magnetoreceptor. It is suggested that the phosphate-binding loop could act as a gate controlling the access to the flavin adenine dinucleotide cofactor depending on the redox state of the protein.


Assuntos
Columbidae , Criptocromos , Animais , Flavina-Adenina Dinucleotídeo , Luz , Campos Magnéticos
4.
Front Chem ; 9: 643796, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34095083

RESUMO

Much of the metabolic molecular machinery responsible for energy transduction processes in living organisms revolves around a series of electron and proton transfer processes. The highly redox active enzymes can, however, also pose a risk of unwanted side reactions leading to reactive oxygen species, which are harmful to cells and are a factor in aging and age-related diseases. Using extensive quantum and classical computational modeling, we here show evidence of a particular superoxide production mechanism through stray reactions between molecular oxygen and a semiquinone reaction intermediate bound in the mitochondrial complex III of the electron transport chain, also known as the cytochrome b c 1 complex. Free energy calculations indicate a favorable electron transfer from semiquinone occurring at low rates under normal circumstances. Furthermore, simulations of the product state reveal that superoxide formed at the Q o -site exclusively leaves the b c 1 complex at the positive side of the membrane and escapes into the intermembrane space of mitochondria, providing a critical clue in further studies of the harmful effects of mitochondrial superoxide production.

5.
Nature ; 594(7864): 535-540, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34163056

RESUMO

Night-migratory songbirds are remarkably proficient navigators1. Flying alone and often over great distances, they use various directional cues including, crucially, a light-dependent magnetic compass2,3. The mechanism of this compass has been suggested to rely on the quantum spin dynamics of photoinduced radical pairs in cryptochrome flavoproteins located in the retinas of the birds4-7. Here we show that the photochemistry of cryptochrome 4 (CRY4) from the night-migratory European robin (Erithacus rubecula) is magnetically sensitive in vitro, and more so than CRY4 from two non-migratory bird species, chicken (Gallus gallus) and pigeon (Columba livia). Site-specific mutations of ErCRY4 reveal the roles of four successive flavin-tryptophan radical pairs in generating magnetic field effects and in stabilizing potential signalling states in a way that could enable sensing and signalling functions to be independently optimized in night-migratory birds.

6.
J Chem Inf Model ; 61(3): 1334-1345, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33617262

RESUMO

Plasmodium falciparum (P. falciparum) is the main parasite known to cause malaria in humans. The antimalarial drug atovaquone is known to inhibit the Qo-site of the cytochrome bc1 complex of P. falciparum, which ultimately blocks ATP synthesis, leading to cell death. Through the years, mutations of the P. falciparum cytochrome bc1 complex, causing resistance to atovaquone, have emerged. The present investigation applies molecular dynamics (MD) simulations to study how the specific mutations Y279S and L282V, known to cause atovaquone resistance in malarial parasites, affect the inhibition mechanism of two known inhibitors. Binding free energy estimates were obtained through free energy perturbation calculations but were unable to confidently resolve the effects of mutations due to the great complexity of the binding environment. Meanwhile, basic mechanistic considerations from the MD simulations provide a detailed characterization of inhibitor binding modes and indicate that the Y279S mutation weakens the natural binding of the inhibitors, while no conclusive effect of the L282V mutation could be observed.


Assuntos
Antimaláricos , Malária Falciparum , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Atovaquona/farmacologia , Atovaquona/uso terapêutico , Citocromos/uso terapêutico , Resistência a Medicamentos , Humanos , Malária Falciparum/tratamento farmacológico , Mutação , Plasmodium falciparum
7.
J Comput Chem ; 42(8): 572-580, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33426653

RESUMO

We are introducing Pep McConst-a software that employs a Monte-Carlo algorithm to construct 3D structures of polypeptide chains which could subsequently be studied as stand-alone macromolecules or complement the structure of known proteins. Using an approach to avoid steric clashes, Pep McConst allows to create multiple structures for a predefined primary sequence of amino acids. These structures could then effectively be used for further structural analysis and investigations. The article introduces the algorithm and describes its user-friendly approach that was made possible through the VIKING online platform. Finally, the manuscript provides several highlight examples where Pep McConst was used to predict the structure of the C-terminal of a known protein, generate a missing bit of already crystallized protein structures and simply generate short polypeptide chains.


Assuntos
Peptídeos/química , Software , Algoritmos , Aminoácidos/química , Fenômenos Biofísicos , Método de Monte Carlo , Conformação Proteica
8.
J Am Chem Soc ; 143(2): 715-723, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33397104

RESUMO

The cytochrome bc1 complex is a transmembrane enzymatic protein complex that plays a central role in cellular energy production and is present in both photosynthetic and respiratory chain organelles. Its reaction mechanism is initiated by the binding of a quinol molecule to an active site, followed by a series of charge transfer reactions between the quinol and protein subunits. Previous work hypothesized that the primary reaction was a concerted proton-coupled electron transfer (PCET) reaction because of the apparent absence of intermediate states associated with single proton or electron transfer reactions. In the present study, the kinetics of the primary bc1 complex PCET reaction is investigated with a vibronically nonadiabatic PCET theory in conjunction with all-atom molecular dynamics simulations and electronic structure calculations. The computed rate constants and relatively high kinetic isotope effects are consistent with experimental measurements on related biomimetic systems. The analysis implicates a concerted PCET mechanism with significant hydrogen tunneling and nonadiabatic effects in the bc1 complex. Moreover, the employed theoretical framework is shown to serve as a general strategy for describing PCET reactions in bioenergetic systems.


Assuntos
Citocromos b/química , Citocromos c1/química , Teoria Quântica , Citocromos b/metabolismo , Citocromos c1/metabolismo , Transporte de Elétrons , Cinética , Prótons , Propriedades de Superfície
9.
J Chem Phys ; 154(3): 035102, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33499614

RESUMO

The mechanism of the magnetic compass sense of migratory songbirds is thought to involve magnetically sensitive chemical reactions of light-induced radical pairs in cryptochrome proteins located in the birds' eyes. However, it is not yet clear whether this mechanism would be sensitive enough to form the basis of a viable compass. In the present work, we report spin dynamics simulations of models of cryptochrome-based radical pairs to assess whether accumulation of nuclear spin polarization in multiple photocycles could lead to significant enhancements in the sensitivity with which the proteins respond to the direction of the geomagnetic field. Although buildup of nuclear polarization appears to offer sensitivity advantages in the more idealized model systems studied, we find that these enhancements do not carry over to conditions that more closely resemble the situation thought to exist in vivo. On the basis of these simulations, we conclude that buildup of nuclear polarization seems unlikely to be a source of significant improvements in the performance of cryptochrome-based radical pair magnetoreceptors.


Assuntos
Núcleo Celular/química , Criptocromos/química , Simulação de Dinâmica Molecular , Radicais Livres/química , Fenômenos Magnéticos
10.
Photochem Photobiol ; 97(2): 243-269, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33369749

RESUMO

This perspective article highlights the challenges in the theoretical description of photoreceptor proteins using multiscale modeling, as discussed at the CECAM workshop in Tel Aviv, Israel. The participants have identified grand challenges and discussed the development of new tools to address them. Recent progress in understanding representative proteins such as green fluorescent protein, photoactive yellow protein, phytochrome, and rhodopsin is presented, along with methodological developments.


Assuntos
Proteínas de Bactérias/química , Proteínas de Fluorescência Verde/química , Modelos Moleculares , Fotorreceptores Microbianos/química , Fitocromo/química , Rodopsina/química , Distribuição de Poisson , Teoria Quântica , Eletricidade Estática
11.
Sci Rep ; 10(1): 20827, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257728

RESUMO

Focused electron beam induced deposition (FEBID) is a powerful technique for 3D-printing of complex nanodevices. However, for resolutions below 10 nm, it struggles to control size, morphology and composition of the structures, due to a lack of molecular-level understanding of the underlying irradiation-driven chemistry (IDC). Computational modeling is a tool to comprehend and further optimize FEBID-related technologies. Here we utilize a novel multiscale methodology which couples Monte Carlo simulations for radiation transport with irradiation-driven molecular dynamics for simulating IDC with atomistic resolution. Through an in depth analysis of [Formula: see text] deposition on [Formula: see text] and its subsequent irradiation with electrons, we provide a comprehensive description of the FEBID process and its intrinsic operation. Our analysis reveals that simulations deliver unprecedented results in modeling the FEBID process, demonstrating an excellent agreement with available experimental data of the simulated nanomaterial composition, microstructure and growth rate as a function of the primary beam parameters. The generality of the methodology provides a powerful tool to study versatile problems where IDC and multiscale phenomena play an essential role.

12.
J Comput Chem ; 41(28): 2429-2439, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-32851682

RESUMO

Ion-induced DNA damage is an important effect underlying ion beam cancer therapy. This article introduces the methodology of modeling DNA damage induced by a shock wave caused by a projectile ion. Specifically it is demonstrated how single- and double strand breaks in a DNA molecule could be described by the reactive CHARMM (rCHARMM) force field implemented in the program MBN Explorer. The entire workflow of performing the shock wave simulations, including obtaining the crucial simulation parameters, is described in seven steps. Two exemplary analyses are provided for a case study simulation serving to: (a) quantify the shock wave propagation and (b) describe the dynamics of formation of DNA breaks. The article concludes by discussing the computational cost of the simulations and revealing the possible maximal computational time for different simulation set-ups.


Assuntos
Quebras de DNA/efeitos da radiação , DNA/química , Sequência de Bases , Simulação por Computador , Ondas de Choque de Alta Energia , Modelos Moleculares , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Radiação Ionizante , Software , Termodinâmica
14.
J Phys Chem Lett ; 11(10): 3866-3870, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32330039

RESUMO

Cryptochrome proteins are thought to be involved in light-sensitive magnetoreception in migratory birds triggered by flavin adenine dinucleotide (FAD) light absorption. A recent study, however, calls into question the ability of vertebrate cryptochrome proteins to bind FAD, rendering them unlikely to function as magnetoreceptive proteins. In this Letter, we investigate the structural changes occurring in Drosophila melanogaster cryptochrome, upon key amino acid mutations, which reduce FAD binding. Through computational analysis we have now suggested why some mutations do not preclude FAD binding in all vertebrate cryptochrome proteins.


Assuntos
Criptocromos/química , Flavina-Adenina Dinucleotídeo/química , Animais , Drosophila melanogaster , Modelos Moleculares , Estrutura Molecular
15.
ACS Omega ; 5(2): 1254-1260, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31984283

RESUMO

Various biochemical and biophysical processes, occurring on multiple time and length scales, can nowadays be studied using specialized software packages on supercomputer clusters. The complexity of such simulations often requires application of different methods in a single study and strong computational expertise. We have developed VIKING, a convenient web platform for carrying out multiscale computations on supercomputers. VIKING allows combining methods in standardized workflows, making complex simulations accessible to a broader biochemical and biophysical society.

16.
J Chem Phys ; 151(19): 194105, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31757147

RESUMO

Magnetic field effects have been measured in various processes involving radical pairs, and such magnetic field effects have provided the basis for a popular hypothesis of magnetoreception in migratory song birds. The spin dynamics of radical pairs exposed to radiofrequency radiation have also been associated with changes in the production of reactive oxygen species within a biological cell, an effect that is potentially harmful. In order to investigate such phenomena theoretically, one needs to employ complex computations which rely on solving stochastic differential equations, which may appear significantly different for slightly different problems relying on spin dynamics. To avoid creating a manifold of specialized tools for various spin chemistry problems, MolSpin has been crafted as general software to handle spin systems of varied complexity. In particular, it permits solving the Liouville-von Neumann equation to obtain the time-evolution of the spin density operator, calculate quantum yields, allows us to utilize semiclassical methods, enables calculation of energy levels in an arbitrary spin system, and predicts resonance frequencies. MolSpin is designed with a high emphasis on extensibility that makes it easy to implement new or extend existing functionality.

17.
J Chem Inf Model ; 59(11): 4868-4879, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31665600

RESUMO

Reactive oxygen species such as superoxide are potentially harmful byproducts of the aerobic metabolism in the inner mitochondrial membrane, and complexes I, II, III of the electron transport chain have been identified as primary sources. The mitochondrial fatty acid b-oxidation pathway may also play a yet uncharacterized role in reactive oxygen species generation, apparently at the level of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) and/or its redox partner electron-transfer flavoprotein (ETF). These enzymes comprise a key pathway through which electrons are sequentially shuttled from several dehydrogenases to the respiratory chain. The exact mechanisms of superoxide production have not been fully established, but a crucial starting point would be the binding of molecular oxygen within one of the protein complexes. The present investigation offers a comprehensive computational approach for the determination of binding modes and characteristic binding times of small molecules inside proteins, which is then used to reveal several O2 binding sites near the flavin adenine dinucleotide cofactor of the ETF enzyme. The binding sites are further characterized to extract the necessary parameters for further studies of possible electron transfer between flavin and O2 leading to radical pair formation and possible superoxide production.


Assuntos
Flavoproteínas Transferidoras de Elétrons/metabolismo , Oxigênio/metabolismo , Sítios de Ligação , Flavoproteínas Transferidoras de Elétrons/química , Flavina-Adenina Dinucleotídeo/metabolismo , Humanos , Cinética , Simulação de Dinâmica Molecular , Ligação Proteica
18.
ACS Appl Mater Interfaces ; 11(45): 41906-41924, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31639302

RESUMO

Graphene foam holds promise for tissue engineering applications. In this study, graphene foam was used as a three-dimension scaffold to evaluate cell attachment, cell morphology, and molecular markers of early differentiation. The aim of this study was to determine if cell attachment and elaboration of an extracellular matrix would be modulated by functionalization of graphene foam with fibronectin, an extracellular matrix protein that cells adhere well to, prior to the establishment of three-dimensional cell culture. The molecular dynamic simulation demonstrated that the fibronectin-graphene interaction was stabilized predominantly through interaction between the graphene and arginine side chains of the protein. Quasi-static and dynamic mechanical testing indicated that fibronectin functionalization of graphene altered the mechanical properties of graphene foam. The elastic strength of the scaffold increased due to fibronectin, but the viscoelastic mechanical behavior remained unchanged. An additive effect was observed in the mechanical stiffness when the graphene foam was both coated with fibronectin and cultured with cells for 28 days. Cytoskeletal organization assessed by fluorescence microscopy demonstrated a fibronectin-dependent reorganization of the actin cytoskeleton and an increase in actin stress fibers. Gene expression assessed by quantitative real-time polymerase chain reaction of 9 genes encoding cell attachment proteins (Cd44, Ctnna1, Ctnnb1, Itga3, Itga5, Itgav, Itgb1, Ncam1, Sgce), 16 genes encoding extracellular matrix proteins (Col1a1, Col2a1, Col3a1, Col5a1, Col6a1, Ecm1, Emilin1, Fn1, Hapln1, Lamb3, Postn, Sparc, Spp1, Thbs1, Thbs2, Tnc), and 9 genes encoding modulators of remodeling (Adamts1, Adamts2, Ctgf, Mmp14, Mmp2, Tgfbi, Timp1, Timp2, Timp3) indicated that graphene foam provided a microenvironment conducive to expression of genes that are important in early chondrogenesis. Functionalization of graphene foam with fibronectin modified the cellular response to graphene foam, demonstrated by decreases in relative gene expression levels. These findings illustrate the combinatorial factors of microscale materials properties and nanoscale molecular features to consider in the design of three-dimensional graphene scaffolds for tissue engineering applications.


Assuntos
Condrócitos/citologia , Condrogênese , Fibronectinas/metabolismo , Grafite/química , Engenharia Tecidual/instrumentação , Tecidos Suporte/química , Animais , Adesão Celular , Moléculas de Adesão Celular , Técnicas de Cultura de Células , Condrócitos/metabolismo , Matriz Extracelular/química , Fibronectinas/química , Camundongos
19.
Methods Enzymol ; 620: 277-314, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31072491

RESUMO

The general field of molecular simulation provides a wide spectrum of methods for studying the structure and function of biomolecules. Depending on the scale and question of interest, appropriate approaches may range from ab initio quantum mechanical calculations (when detailed aspects of and changes in electronic structure must be considered) to Brownian dynamics and coarse-grained molecular dynamics (to track large scale conformational motions, diffusion, and inter-molecular interactions). The entire range of molecular simulation methods has been fruitfully applied to a range of flavoenzymes, allowing researchers to address everything from the specific intermediates involved in the photoreactions of flavin chromophore-containing light sensors, to the very long timescale motions induced by covalent modifications to bound flavin. The unique challenge posed by flavoproteins to all types of molecular simulation arises from the chemistry of the flavin isoalloxazine moiety, which presents an unusually large delocalized electron system which must be carefully treated in order to represent its contributions to the overall behavior of the system. Here we outline the particular considerations required for appropriate treatment of flavoproteins in simulations ranging from electronic structure calculations to long-timescale modeling of flavoprotein conformational transitions.


Assuntos
Flavoproteínas/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Flavinas/química , Conformação Molecular
20.
PLoS One ; 14(3): e0213286, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870450

RESUMO

Recent experiments have reported an effect of weak radiofrequency magnetic fields in the MHz-range on the concentrations of reactive oxygen species (ROS) in living cells. Since the energy that could possibly be deposited by the radiation is orders of magnitude smaller than the energy of molecular thermal motion, it was suggested that the effect was caused by the interaction of RF magnetic fields with transient radical pairs within the cells, affecting the ROS formation rates through the radical pair mechanism. It is, however, at present not entirely clear how to predict RF magnetic field effects at certain field frequency and intensity in nanoscale biomolecular systems. We suggest a possible recipe for interpreting the radiofrequency effects in cells by presenting a general workflow for calculation of the reactive perturbations inside a cell as a function of RF magnetic field strength and frequency. To justify the workflow, we discuss the effects of radiofrequency magnetic fields on generic spin systems to particularly illustrate how the reactive radicals could be affected by specific parameters of the experiment. We finally argue that the suggested workflow can be used to predict effects of radiofrequency magnetic fields on radical pairs in biological cells, which is specially important for wireless recharging technologies where one has to know of any harmful effects that exposure to such radiation might cause.


Assuntos
Células/efeitos da radiação , Campos Eletromagnéticos/efeitos adversos , Modelos Teóricos , Lesões por Radiação/etiologia , Espécies Reativas de Oxigênio/metabolismo , Células Cultivadas , Humanos
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