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1.
Cell Mol Biol Lett ; 27(1): 3, 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34979905

RESUMO

BACKGROUND: Calcitriol (an active metabolite of vitamin D) modulates the expression of hundreds of human genes by activation of the vitamin D nuclear receptor (VDR). However, VDR-mediated transcriptional modulation does not fully explain various phenotypic effects of calcitriol. Recently a fast non-genomic response to vitamin D has been described, and it seems that mitochondria are one of the targets of calcitriol. These non-classical calcitriol targets open up a new area of research with potential clinical applications. The goal of our study was to ascertain whether calcitriol can modulate mitochondrial function through regulation of the potassium channels present in the inner mitochondrial membrane. METHODS: The effects of calcitriol on the potassium ion current were measured using the patch-clamp method modified for the inner mitochondrial membrane. Molecular docking experiments were conducted in the Autodock4 program. Additionally, changes in gene expression were investigated by qPCR, and transcription factor binding sites were analyzed in the CiiiDER program. RESULTS: For the first time, our results indicate that calcitriol directly affects the activity of the mitochondrial large-conductance Ca2+-regulated potassium channel (mitoBKCa) from the human astrocytoma (U-87 MG) cell line but not the mitochondrial calcium-independent two-pore domain potassium channel (mitoTASK-3) from human keratinocytes (HaCaT). The open probability of the mitoBKCa channel in high calcium conditions decreased after calcitriol treatment and the opposite effect was observed in low calcium conditions. Moreover, using the AutoDock4 program we predicted the binding poses of calcitriol to the calcium-bound BKCa channel and identified amino acids interacting with the calcitriol molecule. Additionally, we found that calcitriol influences the expression of genes encoding potassium channels. Such a dual, genomic and non-genomic action explains the pleiotropic activity of calcitriol. CONCLUSIONS: Calcitriol can regulate the mitochondrial large-conductance calcium-regulated potassium channel. Our data open a new chapter in the study of non-genomic responses to vitamin D with potential implications for mitochondrial bioenergetics and cytoprotective mechanisms.


Assuntos
Calcitriol , Canais de Potássio Ativados por Cálcio de Condutância Alta , Calcitriol/metabolismo , Calcitriol/farmacologia , Cálcio/metabolismo , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Alta/farmacologia , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Técnicas de Patch-Clamp
2.
Methods Mol Biol ; 2376: 399-416, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34845623

RESUMO

The physics-based united-residue (UNRES) model of proteins ( www.unres.pl ) has been designed to carry out large-scale simulations of protein folding. The force field has been derived and parameterized based on the principles of statistical-mechanics, which makes it independent of structural databases and applicable to treat nonstandard situations such as, proteins that contain D-amino-acid residues. Powered by Langevin dynamics and its replica-exchange extensions, UNRES has found a variety of applications, including ab initio and database-assisted protein-structure prediction, simulating protein-folding pathways, exploring protein free-energy landscapes, and solving biological problems. This chapter provides a summary of UNRES and a guide for potential users regarding the application of the UNRES package in a variety of research tasks.


Assuntos
Conformação Proteica , Entropia , Simulação de Dinâmica Molecular , Dobramento de Proteína , Proteínas
3.
Biomolecules ; 11(9)2021 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-34572559

RESUMO

Molecular dynamics with coarse-grained models is nowadays extensively used to simulate biomolecular systems at large time and size scales, compared to those accessible to all-atom molecular dynamics. In this review article, we describe the physical basis of coarse-grained molecular dynamics, the coarse-grained force fields, the equations of motion and the respective numerical integration algorithms, and selected practical applications of coarse-grained molecular dynamics. We demonstrate that the motion of coarse-grained sites is governed by the potential of mean force and the friction and stochastic forces, resulting from integrating out the secondary degrees of freedom. Consequently, Langevin dynamics is a natural means of describing the motion of a system at the coarse-grained level and the potential of mean force is the physical basis of the coarse-grained force fields. Moreover, the choice of coarse-grained variables and the fact that coarse-grained sites often do not have spherical symmetry implies a non-diagonal inertia tensor. We describe selected coarse-grained models used in molecular dynamics simulations, including the most popular MARTINI model developed by Marrink's group and the UNICORN model of biological macromolecules developed in our laboratory. We conclude by discussing examples of the application of coarse-grained molecular dynamics to study biologically important processes.


Assuntos
Modelos Teóricos , Simulação de Dinâmica Molecular , DNA/química , Hidrodinâmica , Ligação de Hidrogênio , Cinética , Proteínas Mutantes/química , Fosforilação , Dobramento de Proteína , Proteínas/química , Proteínas/metabolismo
4.
J Mol Graph Model ; 108: 108008, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34419932

RESUMO

The UNited RESidue (UNRES) force field was tested in the 14th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP14), in which larger oligomeric and multimeric targets were present compared to previous editions. Three prediction modes were tested (i) ab initio (the UNRES group), (ii) contact-assisted (the UNRES-contact group), and (iii) template-assisted (the UNRES-template group). For most of the targets, the contact restraints were derived from the server models top-ranked by the DeepQA method, while the DNCON2 method was used for 11 targets. Our consensus-fragment procedure was used to run template-assisted predictions. Each group also processed the Nuclear Magnetic Resonance (NMR)- and Small Angle X-Ray Scattering (SAXS)-data assisted targets. The average Global Distance Test Total Score (GDT_TS) of the 'Model 1' predictions were 29.17, 39.32, and 56.37 for the UNRES, UNRES-contact, and UNRES-template predictions, respectively, increasing by 0.53, 2.24, and 3.76, respectively, compared to CASP13. It was also found that the GDT_TS of the UNRES models obtained in ab initio mode and in the contact-assisted mode decreases with the square root of chain length, while the exponent in this relationship is 0.20 for the UNRES-template group models and 0.11 for the best performing AlphaFold2 models, which suggests that incorporation of database information, which stems from protein evolution, brings in long-range correlations, thus enabling the correction of force-field inaccuracies.


Assuntos
Proteínas , Bases de Dados Factuais , Conformação Proteica , Espalhamento a Baixo Ângulo , Difração de Raios X
5.
Proteins ; 89(12): 1800-1823, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34453465

RESUMO

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70-75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70-80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands.


Assuntos
Biologia Computacional/métodos , Modelos Moleculares , Proteínas , Software , Sítios de Ligação , Simulação de Acoplamento Molecular , Domínios e Motivos de Interação entre Proteínas , Proteínas/química , Proteínas/metabolismo , Análise de Sequência de Proteína
6.
J Chem Theory Comput ; 17(5): 3203-3220, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33909430

RESUMO

Apart from being the most common mechanism of regulating protein function and transmitting signals throughout the cell, phosphorylation has an ability to induce disorder-to-order transition in an intrinsically disordered protein. In particular, it was shown that folding of the intrinsically disordered protein, eIF4E-binding protein isoform 2 (4E-BP2), can be induced by multisite phosphorylation. Here, the principles that govern the folding of phosphorylated 4E-BP2 (pT37pT46 4E-BP218-62) are investigated by analyzing canonical and replica exchange molecular dynamics trajectories, generated with the coarse-grained united-residue force field, in terms of local and global motions and the time dependence of formation of contacts between Cαs of selected pairs of residues. The key residues involved in the folding of the pT37pT46 4E-BP218-62 are elucidated by this analysis. The correlations between local and global motions are identified. Moreover, for a better understanding of the physics of the formation of the folded state, the experimental structure of the pT37pT46 4E-BP218-62 is analyzed in terms of a kink (heteroclinic standing wave solution) of a generalized discrete nonlinear Schrödinger equation. It is shown that without molecular dynamics simulations the kinks are able to identify not only the phosphorylated sites of protein, the key players in folding, but also the reasons for the weak stability of the pT37pT46 4E-BP218-62.


Assuntos
Proteínas Intrinsicamente Desordenadas/química , Dobramento de Proteína , Simulação de Dinâmica Molecular , Fosforilação , Termodinâmica
7.
J Mol Graph Model ; 103: 107802, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33246194

RESUMO

Immune system plays essential role in functioning of higher organisms. Its hyperactivity can lead to autoimmune diseases or even anaphylactic shock while hypoactivity leads to proneness to infections or even cancer. T-cells play crucial role in immunity mechanisms and their activation and inhibition is strictly controlled by the regulatory proteins, such as CD28 and CTLA-4. Activity of these proteins is controlled by a pair of ligands, named CD80 and CD86, which can non-covalently bound to their receptors. While structure of human CTLA-4-CD86 complex in known, there is still no available structure for the CD28-CD86 system. To obtain the reliable structure of CD28-CD86 complex we first validated our methodology on the CTLA-4-CD86 system. Then coarse-grained UNRES-dock molecular docking simulation was performed followed by all-atom molecular dynamics simulations. As a result, we obtained a complete CD28-CD86 complex structure on atomistic level, in which interaction interface is consistent with available data. We also determined the kinetic properties for CTLA4-CD86 and CD28-CD86 complexes with use of coarse-grained model and determined the key residues for complex formation with use of Robetta, PPCheck and HawkDock servers. Our results not only verify high accuracy of the UNRES-dock method, but also provide a highly reliable model of the CD28-CD86 complex, which can be used in further studies and drug design.


Assuntos
Antígeno B7-2/química , Antígenos CD28 , Imunoconjugados , Abatacepte , Antígenos CD , Antígenos CD28/química , Humanos , Glicoproteínas de Membrana , Simulação de Acoplamento Molecular , Conformação Proteica
8.
Int J Mol Sci ; 21(16)2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32824145

RESUMO

Human cystatin C (HCC), a cysteine-protease inhibitor, exists as a folded monomer under physiological conditions but has the ability to self-assemble via domain swapping into multimeric states, including oligomers with a doughnut-like structure. The structure of the monomeric HCC has been solved by X-ray crystallography, and a covalently linked version of HCC (stab-1 HCC) is able to form stable oligomeric species containing 10-12 monomeric subunits. We have performed molecular modeling, and in conjunction with experimental parameters obtained from atomic force microscopy (AFM), transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) measurements, we observe that the structures are essentially flat, with a height of about 2 nm, and the distance between the outer edge of the ring and the edge of the central cavity is ~5.1 nm. These dimensions correspond to the height and diameter of one stab-1 HCC subunit and we present a dodecamer model for stabilized cystatin C oligomers using molecular dynamics simulations and experimentally measured parameters. Given that oligomeric species in protein aggregation reactions are often transient and very highly heterogeneous, the structural information presented here on these isolated stab-1 HCC oligomers may be useful to further explore the physiological relevance of different structural species of cystatin C in relation to protein misfolding disease.


Assuntos
Cistatina C/química , Simulação de Dinâmica Molecular , Humanos , Dobramento de Proteína , Multimerização Proteica , Estabilidade Proteica
9.
Prog Mol Biol Transl Sci ; 170: 73-122, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32145953

RESUMO

In this chapter the scale-consistent approach to the derivation of coarse-grained force fields developed in our laboratory is presented, in which the effective energy function originates from the potential of mean force of the system under consideration and embeds atomistically detailed interactions in the resulting energy terms through use of Kubo's cluster-cumulant expansion, appropriate selection of the major degrees of freedom to be averaged out in the derivation of analytical approximations to the energy terms, and appropriate expression of the interaction energies at the all-atom level in these degrees of freedom. Our approach enables the developers to find correct functional forms of the effective coarse-grained energy terms, without having to import them from all-atom force fields or deriving them on a heuristic basis. In particular, the energy terms derived in such a way exhibit correct dependence on coarse-grained geometry, in particular on site orientation. Moreover, analytical formulas for the multibody (correlation) terms, which appear to be crucial for coarse-grained modeling of many of the regular structures such as, e.g., protein α-helices and ß-sheets, can be derived in a systematic way. Implementation of the developed theory to the UNIfied COarse-gRaiNed (UNICORN) model of biological macromolecules, which consists of the UNRES (for proteins), NARES-2P (for nucleic acids), and SUGRES-1P (for polysaccharides) components, and is being developed in our laboratory is described. Successful applications of UNICORN to the prediction of protein structure, simulating the folding and stability of proteins and nucleic acids, and solving biological problems are discussed.


Assuntos
Biopolímeros/química , Simulação de Dinâmica Molecular , DNA/química , Proteínas de Choque Térmico HSP70/química , Hidrodinâmica , Ligação de Hidrogênio , Cinética , Substâncias Macromoleculares/química , Ferramenta de Busca , Telômero/metabolismo , Termodinâmica
10.
J Chem Inf Model ; 60(3): 1844-1864, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-31999919

RESUMO

The method for protein-structure prediction, which combines the physics-based coarse-grained UNRES force field with knowledge-based modeling, has been developed further and tested in the 13th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP13). The method implements restraints from the consensus fragments common to server models. In this work, the server models to derive fragments have been chosen on the basis of quality assessment; a fully automatic fragment-selection procedure has been introduced, and Dynamic Fragment Assembly pseudopotentials have been fully implemented. The Global Distance Test Score (GDT_TS), averaged over our "Model 1" predictions, increased by over 10 units with respect to CASP12 for the free-modeling category to reach 40.82. Our "Model 1" predictions ranked 20 and 14 for all and free-modeling targets, respectively (upper 20.2% and 14.3% of all models submitted to CASP13 in these categories, respectively), compared to 27 (upper 21.1%) and 24 (upper 18.9%) in CASP12, respectively. For oligomeric targets, the Interface Patch Similarity (IPS) and Interface Contact Similarity (ICS) averaged over our best oligomer models increased from 0.28 to 0.36 and from 12.4 to 17.8, respectively, from CASP12 to CASP13, and top-ranking models of 2 targets (H0968 and T0997o) were obtained (none in CASP12). The improvement of our method in CASP13 over CASP12 was ascribed to the combined effect of the overall enhancement of server-model quality, our success in selecting server models and fragments to derive restraints, and improvements of the restraint and potential-energy functions.


Assuntos
Algoritmos , Proteínas , Biologia Computacional , Consenso , Modelos Moleculares , Conformação Proteica
12.
Proteins ; 87(12): 1283-1297, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31569265

RESUMO

With the advance of experimental procedures obtaining chemical crosslinking information is becoming a fast and routine practice. Information on crosslinks can greatly enhance the accuracy of protein structure modeling. Here, we review the current state of the art in modeling protein structures with the assistance of experimentally determined chemical crosslinks within the framework of the 13th meeting of Critical Assessment of Structure Prediction approaches. This largest-to-date blind assessment reveals benefits of using data assistance in difficult to model protein structure prediction cases. However, in a broader context, it also suggests that with the unprecedented advance in accuracy to predict contacts in recent years, experimental crosslinks will be useful only if their specificity and accuracy further improved and they are better integrated into computational workflows.


Assuntos
Biologia Computacional/métodos , Reagentes para Ligações Cruzadas/química , Modelos Moleculares , Conformação Proteica , Proteínas/química , Algoritmos , Cromatografia Líquida , Modelos Químicos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
13.
J Phys Chem B ; 123(37): 7829-7839, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31454484

RESUMO

The physics-based UNRES coarse-grained force field for the simulations of protein structure and dynamics has been extended to treat membrane proteins. The lipid bilayer has been modeled by introducing a continuous nonpolar phase with the water-interface region of appropriate thickness. The potentials for average electrostatic and correlation interactions of the peptide groups have been rescaled to account for the reduction of the dielectric permittivity compared to the water phase and new potentials for protein side-chain-side-chain interactions inside and across the lipid phase have been introduced. The model was implemented in the UNRES package for coarse-grained simulations of proteins, and the package with the new functionality was tested for total energy conservation and thermostat behavior in microcanonical and canonical molecular dynamics simulations runs, respectively. The method was validated by running unrestricted ab initio blind-prediction tests of 10 short α-helical membrane proteins, all runs started from the extended structures. The modified UNRES force field was able to predict correctly the overall folds of the membrane proteins studied.


Assuntos
Bicamadas Lipídicas/química , Proteínas de Membrana/química , Simulação de Dinâmica Molecular
14.
J Mol Graph Model ; 92: 154-166, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31376733

RESUMO

The recent NEWCT-9P version of the coarse-grained UNRES force field for proteins, with scale-consistent formulas for the local and correlation terms, has been tested in the CASP13 experiment of the blind-prediction of protein structure, in the ab initio, contact-assisted, and data-assisted modes. Significant improvement of the performance has been observed with respect to the CASP11 and CASP12 experiments (by over 10 GDT_TS units for the ab initio mode predictions and by over 15 GDT_TS units for the contact-assisted prediction, respectively), which is a result of introducing scale-consistent terms and improved handling of contact-distance restraints. As in previous CASP exercises, UNRES ranked higher in the free modeling category than in the general category that included template based modeling targets. Use of distance restraints from the predicted contacts, albeit many of them were wrong, resulted in the increase of GDT_TS by over 8 units on average and introducing sparse restraints from small-angle X-ray/neutron scattering and chemical cross-link-mass-spectrometry experiments, and ambiguous restraints from nuclear magnetic resonance experiments has also improved the predictions by 8.6, 9.7, and 10.7 GDT_TS units on average, respectively.


Assuntos
Modelos Moleculares , Conformação Proteica , Proteínas/química , Algoritmos , Proteínas da Matriz do Complexo de Golgi/química , Peptídeos/química
15.
J Phys Chem B ; 123(27): 5721-5729, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31194908

RESUMO

Phosphorylated proteins take part in many signaling pathways and play a key role in homeostasis regulation. The all-atom force fields enable us to study the systems containing phosphorylated proteins, but they are limited to short time scales. In this paper, we report the extension of the physics-based coarse-grained UNRES force field to treat systems with phosphorylated amino-acid residues. To derive the respective potentials, appropriate physics-based analytical expressions were fitted to the potentials of mean force of systems modeling phosphorylated amino-acid residues computed in our previous work and implemented in UNRES. The extended UNRES performed well in ab initio simulations of two miniproteins containing phosphorylated residues, strongly suggesting that realistic large-scale simulations of processes involving phosphorylated proteins, especially signaling processes, are now possible.


Assuntos
Peptídeos/metabolismo , Modelos Moleculares , Peptídeos/química , Fosforilação , Teoria Quântica
16.
J Chem Phys ; 150(15): 155104, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31005069

RESUMO

The general theory of the construction of scale-consistent energy terms in the coarse-grained force fields presented in Paper I of this series has been applied to the revision of the UNRES force field for physics-based simulations of proteins. The potentials of mean force corresponding to backbone-local and backbone-correlation energy terms were calculated from the ab initio energy surfaces of terminally blocked glycine, alanine, and proline, and the respective analytical expressions, derived by using the scale-consistent formalism, were fitted to them. The parameters of all these potentials depend on single-residue types, thus reducing their number and preventing over-fitting. The UNRES force field with the revised backbone-local and backbone-correlation terms was calibrated with a set of four small proteins with basic folds: tryptophan cage variant (TRP1; α), Full Sequence Design (FSD; α + ß), villin headpiece (villin; α), and a truncated FBP-28 WW-domain variant (2MWD; ß) (the NEWCT-4P force field) and, subsequently, with an enhanced set of 9 proteins composed of TRP1, FSD, villin, 1BDC (α), 2I18 (α), 1QHK (α + ß), 2N9L (α + ß), 1E0L (ß), and 2LX7 (ß) (the NEWCT-9P force field). The NEWCT-9P force field performed better than NEWCT-4P in a blind-prediction-like test with a set of 26 proteins not used in calibration and outperformed, in a test with 76 proteins, the most advanced OPT-WTFSA-2 version of UNRES with former backbone-local and backbone-correlation terms that contained more energy terms and more optimizable parameters. The NEWCT-9P force field reproduced the bimodal distribution of backbone-virtual-bond angles in the simulated structures, as observed in experimental protein structures.

17.
Methods Mol Biol ; 1958: 133-146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30945217

RESUMO

The secondary structure of proteins results from both local and long-range interactions, the latter being primarily backbone hydrogen bonding. In this chapter, based on our recent work, we suggest that the striking regularity of secondary structure can be described, in a semi-analytical manner, in terms of Kubo cluster cumulants (corresponding to the expansion of the protein's potential of mean force) that originate from the coupling between the backbone-local and backbone-electrostatic interactions. This finding is illustrated by the analysis of the Protein Data Bank statistics. Examples demonstrating the importance of the coupling terms in coarse-grained treatment of proteins are also presented.


Assuntos
Motivos de Aminoácidos , Biologia Computacional/métodos , Estrutura Secundária de Proteína , Proteínas/química , Bases de Dados de Proteínas , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Conformação Proteica , Termodinâmica
18.
Biopolymers ; 110(7): e23252, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30667535

RESUMO

Heparin is a key player in cell signaling via its physical interactions with protein targets in the extracellular matrix. However, basic molecular level understanding of these highly biologically relevant intermolecular interactions is still incomplete. In this study, for the first time, microsecond-scale MD simulations are reported for a complex between fibroblast growth factor 1 and heparin. We rigorously analyze this molecular system in terms of the conformational space, structural, energetic, and dynamic characteristics. We reveal that the conformational selection mechanism of binding denotes a recognition specificity determinant. We conclude that the length of the simulation could be crucial for evaluation of some of the analyzed parameters. Our data provide novel significant insights into the interactions in the fibroblast growth factor 1 complex with heparin, in particular, and into the physical-chemical nature of protein-glycosaminoglycan systems in general, which have potential applicability for biomaterials development in the area of regenerative medicine.


Assuntos
Fator 1 de Crescimento de Fibroblastos/química , Heparina/química , Simulação de Dinâmica Molecular , Sítios de Ligação , Fator 1 de Crescimento de Fibroblastos/metabolismo , Heparina/metabolismo , Humanos , Cinética , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Termodinâmica
19.
J Comput Chem ; 39(28): 2360-2370, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30306573

RESUMO

Based on the coarse-grained UNRES and NARES-2P models of proteins and nucleic acids, respectively, developed in our laboratory, in this work we have developed a coarse-grained model of systems containing proteins and nucleic acids. The UNRES and NARES-2P effective energy functions have been applied to the protein and nucleic-acid components of a system, respectively, while protein-nucleic-acid interactions have been described by the respective coarse-grained potentials developed in our recent work (Yin et al., J. Chem Theory Comput. 2015, 11, 1792). The Debye-Hückel screening has been applied to the electrostatic-interaction energy between the phosphate groups and charged amino-acid side chains. The model has been integrated into the UNRES package for coarse-grained molecular dynamics simulations of proteins and the implementation has been tested for energy conservation in microcanonical molecular dynamics runs and for temperature conservation in canonical molecular dynamics runs. Two case studies were performed: (i) the dynamics of the Ku protein heterodimer bound to DNA, for which it was found that the Ku70/Ku80 protein complex plays an active role in DNA repairing and (ii) conformational changes of the multiple antibiotic resistance (MarA) protein occurring during DNA binding, for which the functionally important motions occurring during this process were identified. © 2018 Wiley Periodicals, Inc.


Assuntos
DNA/química , Simulação de Dinâmica Molecular , Proteínas/química , Conformação Proteica , Temperatura
20.
J Phys Chem B ; 122(34): 8166-8173, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30080414

RESUMO

The stability of DNA is crucial for the existence of most living organisms. Even a single DNA break can lead to serious problems, including cell death. In this work the position specificity of single strand breaks (SSB) and the stability of short DNA fragments of various lengths and sequence repetitions (d(AT)30, d(ATGC)15, d(GC)30, d(TTAGG)12, d(TTAGGG)10, and d(TTTAGGG)9 with SSBs and d(GC) with 2-60 repetitions without SSBs) were examined, by performing a series of steered molecular dynamics simulations using the coarse-grained NARES-2P force field. Our results show that the stability of DNA with a SSB strongly depends on the position of the break, and that the minimum length of DNA required for stability is sequence dependent. d(GC)30 with an SSB in position x was found to be less resistant to stretching than d(GC) x without SSB, where x is the number of d(GC) repetitions. DNA sequences with longer repeated fragments (such as telomeres) exhibit greater stability in the presence of breaks positioned at the beginning of the chain, which could constitute a cellular defense mechanism against DNA damage.


Assuntos
Quebras de DNA de Cadeia Simples , DNA/química , Fenômenos Bioquímicos , Ligação de Hidrogênio , Fenômenos Mecânicos , Simulação de Dinâmica Molecular , Estrutura Molecular
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