Conformational stability of PCID2 upon DSS1 bi

Conformational stability of PCID2 upon DSS1 bi
Conformational stability of PCID2 upon DSS1 bi

ORIGINAL PAPER

Conformational stability of PCID2upon DSS1binding with molecular dynamics simulation

Qianjun Liu1,2&Guodong Hu1&Zanxia Cao1&Jihua Wang1,3&Haifeng Chen4

Received:22September2014/Accepted:23March2015

#Springer-Verlag Berlin Heidelberg2015

Abstract DSS1is a small acidic intrinsically disordered pro-tein(IDP)that can fold upon binding with PCID2TREX-2. The resulting complex plays a key role in mRNA export. However,the binding mechanism between DSS1and PCID2 is unsolved.Here,three independent500-ns molecular dy-namics(MD)simulations were performed to study the DSS1–PCID2binding mechanism by comparing apo-PCID2 and bound PCID2.The results show that the conformational variation of bound PCID2is smaller than that of apo-PCID2, especially in the binding domain of two helices(helix IV and VIII).The probability of coil formation between helix III and helix IVof bound PCID2increases,and a short anti-parallelβ-sheet forms upon DSS1binding.The decomposition of bind-ing free energy into protein and residue pairs suggests that electrostatic and hydrophobic interactions play key roles in the recognition between DSS1and PCID2.There is a hydro-phobic core of seven residues in DSS1favorable to the bind-ing of PCID2.These analytical methods can be used to reveal the recognition mechanisms of other IDPs and their partners. Keywords PCID2protein.Molecular dynamics simulation. Conformational changes.Binding free energy

Introduction

Intrinsically disordered proteins(IDPs)are a class of protein that lacks well-structured three dimensional(3D)folds entire-ly or partly under physiological conditions[1–5].IDPs are ubiquitous and are associated with many significant biological functions.For example,IDPs play key roles in transcriptional regulation and other cellular processes.Furthermore,IDPs are implicated in human diseases[6–8]such as neurodegenerative diseases and cancer[9–11].IDPs lack the single unique fold of structured proteins,but their conformations are far from ran-dom.It is believed that their flexibility is likely the reason that IDPs,for example DSS1,often evolve to interact with multi-ple similar partners[12–15].The flexibility of IDPs also con-fers a functional advantage;for example,it is easier for IDPs than globular proteins to bind to a polypeptide in an extended conformation with a larger interface area per residue[16]. However,few of the hypotheses as to why disorder is benefi-cial have been tested experimentally and little experimental data exist on the details of the binding reaction mechanisms of IDPs[17].

In recent years,much effort has been directed towards researching IDPs experimentally.Another,more fundamental, approach to the study of IDPs may be to use molecular dy-namics(MD)simulations directly[1,18,19].MD simulations test minute changes and ascertain the dynamic properties of

a Electronic supplementary material The online version of this article

(doi:10.1007/s00894-015-2664-7)contains supplementary material,

which is available to authorized users.

*Guodong Hu

xzszhgd@https://www.360docs.net/doc/e915322879.html,

Jihua Wang

jhw25336@https://www.360docs.net/doc/e915322879.html,

1Shandong Provincial Key Laboratory of Functional Macromolecular

Biophysics,College of Physics and Electronic Information,Dezhou

University,Dezhou253023,China

2College of Life Science,Shandong Normal University,Jinan250014,

China

3The State Key Laboratory of Bioelectronics,Southeast University,

Nanjing210096,China

4State Key Laboratory of Microbial Metabolism,Department of

Bioinformatics and Biostatistics,College of Life Sciences and

Biotechnology,Shanghai Jiaotong University,Shanghai200240,

China

J Mol Model (2015) 21:127

DOI10.1007/s00894-015-2664-7

system,and hence have become an effective method in the field of biomolecule folding and unfolding [20,21],and are expected to provide more accurate structural ensembles [8].The IDP DSS1[22,23]is a small acidic protein that regu-lates the functional integrity of multiple protein complexes involved in diverse biological pathways,and has been shown to associate with a wide range of conserved complexes includ-ing the 19S proteosome lid,and the CSN,eIF3,BRCA2,and Integrator complexes [24–27].A complex of DSS1and PCID2as a component of TREX-2complex plays an impor-tant role in mRNA export [28–31].One of the functions of DSS1is to stabilize the structure of PCID2[32,33,30].The crystal structure of the PCID2-DSS1complex was reported in 2012(PDB ID:3T5X)[34].As shown in Fig.1,the PCID2protein has nine α-helices and three strands of antiparallel β-sheets.The apo-DSS1consists of a helix (X)and a coil.When DSS1binds to PCID2,it forms an antipar-allel β-sheet between helix III and IV of the PCID2superhe-lical domain.The DSS1C-terminal helix bound to PCID2,the conserved hydrophobic interacting face of this DSS1helix (Phe52,Leu56and Leu60)binds in the cleft between helix VII and VIII of the PCID2C-terminal winged-helix domain.Two conserved tryptophans (39and 43)are buried in the PCID2domain and appear crucial to this hydrophobic inter-action [34].

Experimental results have indicated that the function of DSS1protein is to stabilize the structure of PCID2[26,34,32].However,several interesting questions arise from the ex-perimental results.Such as,how does DSS1influence the con-formation of PCID2?What is the binding mode between PCID2and DSS1?To answer these questions,we utilized MD simulations to analyze the relationship between binding and conformational change in the PCID2-DSS1complex.The conformational changes were assessed via the root mean square deviations (RMSD)of C αatoms,the root mean square fluctuation (RMSF)of C αatoms,principal components analy-sis (PCA)and tertiary contacts.The mechanism of conforma-tional change was analyzed via the probability of helix forma-tion and the decomposition of binding free energy between

DSS1and PCID2.The results indicated that the PCID2without DSS1was less stable than the PCID2-DSS1complex.

Methods

System setups

In this work,three MD simulations were performed.The starting structures of MD simulation were extracted from the crystallographic structure of the PCID2and DSS1complex (PDB ID:3T5X)[34].The residues from the crystallographic structure used were 205–399for apo-PCID2,and 38-67for apo-DSS1.The proteins were solvated in rectangular TIP4P water [35]boxes with the minimum solute-box boundary dis-tance set to 1.0nm.To neutralize the systems,the appropriate numbers of counterions were added.The OPLS-AA force field [36],suggested for use in the MD simulation of IDPs [37],was applied to obtain the force field parameters for pro-teins,water molecules and ions.Molecular dynamics simulations

All MD simulations were performed using the GROMACS software package [38].The particle-mesh Ewald method [39,40]was used to treat long-range electrostatic interactions.The cutoff for the long-range electrostatic and van der Waals en-ergy was set to 0.9nm.All the covalent bonds involving hydrogen atoms were fixed using the LINCS algorithm [38].During MD simulation,the integration time step was set to 2fs.The Berendsen algorithm was used at a constant temper-ature of 300K and a constant pressure of 1atm.Energy min-imization with the steepest descents method was performed to relax the ions and water molecules.To avoid unnecessary distortion of the protein when the MD simulation was started,a 300-ps equilibration run was first performed,in which posi-tional restraints were imposed on the solute atoms.During the equilibration run,the temperature was raised from 50to 300K.To compare the difference between apo-PCID2and bound PCID2,we simulated three systems of 500ns each for apo-PCID2,apo-DSS1,and bound PCID2;300ns simula-tions were found sufficient for these systems to reach equilib-rium at room temperature,and1.5μs trajectories were collect-ed for all simulated systems.

Residue-inhibitor interaction decomposition

To understand the PCID2and DSS1interaction in more detail,the interaction energy between the protein and each residue was calculated using the theory of free energy decomposition [41].This approach has been successful in analyzing protein –ligand or protein –protein interactions [42–44].The binding interaction of each protein-residue pair (ΔG pro ‐res )

includes

Fig.1Structure of the PCID2-DSS1complex shown in ribbon representation

127 Page 2of 9J Mol Model (2015) 21:127

four terms:van der Waals energy (ΔE vdw ),electrostatic ener-gy (ΔE ele ),polar solvation contribution (ΔG pol )and nonpolar solvation contribution (ΔG nonpol ).

ΔG pro ‐res ?ΔE ele tΔE vdw tΔG pol tΔG nonpol

e1T

All energy components were calculated using 150snap-shots extracted evenly from the last 300ns of the MD simu-lation.ΔE ele and ΔE vdw were calculated with AMBER force field (FF03)[45],ΔG pol was calculated by generalized Born (GB)methods implemented in SANDER.ΔG nonpol was de-termined with Eq.2.G nonpol ?γSASA tβ

e2T

where SASA is the solvent-accessible surface area deter-mined using the LCPO model [46].The values γand βare empirical constants and were set 0.005kcal mol ?1??2)and 0,respectively [47].Data analysis

Tertiary and binding contacts were calculated using the native contacts patch of the RMSD Trajectory Tool in VMD.Two nonadjacent residues are in tertiary contact when their C αatoms are closer than 6.5?.Two atoms (one in PCID2and the other in DSS1)are in binding contact when their distance is less than 3.5?.Here,we used the fraction of native tertiary

contacts (Qf)and native binding contacts (Qb)to monitor unfolding and unbinding kinetics.Unfolding kinetics were fitted in Origin 7.5[48].

Results and discussion

Stability of apo-PCID2,apo-DSS1and PCID2-DSS1complexes

In order to evaluate the stability of the MD simulation,we calculated the RMSDs and the radius of gyration (Rg)of C αatoms of the protein (Fig.2a,b ).The systems of the complex and PCID2reached a stable state after 200ns MD simulation,where the RMSDs and Rg values converged to an averaged value.The averaged RMSDs were 0.24,0.35and 0.64nm for the complex,PCID2and DSS1,respectively.The RMSD val-ue of the PCID2–DSS1complex was the smallest among the three systems,and that of DSS1the largest.The standard deviations were 0.015,0.028,and 0.159for the complex,PCID2and DSS1,respectively.This implies that the complex is more stable than PCID2and DSS1individually.This is in accordance with the nature of apo-DSS1as an IDP.The last 300ns of the MD trajectories of the three systems were used for subsequent analysis.

The RMSF of the C α,which is commonly used to observe the fluctuation of each residue,was plotted along the

residue

Fig.2a Root-mean-square de-viation (RMSD)of C αatoms relative to their crystal structure as a function of molecular dynamics (MD)simulation time.b Radius of gyration of C αatoms as a function of MD simulation time.c ,d Root mean square fluctuation (RMSF)of C αversus residue number for PCID2(c )and DSS1(d )

J Mol Model (2015) 21:127 Page 3of 9 127

sequence in Fig.2c,d .The experimental RMSFs were calcu-lated from the B-factor of atoms in the crystallographic PDB file using the equation RMSF ?3B I =8π2eT1

2and are also shown in Fig.2c,d .Residues located at the binding site are

marked as squares.The calculated RMSFs for the complex were lower than the experimental values;however,fluctuation in the binding site for the complex was similar to that of experimental data,and differed from the data of unbound pro-tein (apo-PCID2and apo-DSS1).The RMSF of each C αatom in the PCID2-DSS1complex was obviously smaller than the corresponding atoms in apo-PCID2and apo-DSS1,especially in the binding site,i.e.,resides 252–271and residues 323–350(Fig.2c ).This implies that the equilibrated MD simulation of complex is in accordance with the experimental data and the binding between PCID2and DSS1improves the stability of the structure,especially for residues near the binding site.PCA were performed based on the last 300ns MD simula-tion trajectory.Figure 3shows a plot of the eigenvalues ob-tained from diagonalization of the covariance matrix of fluc-tuations of the C αatom,depicted in decreasing order versus the corresponding eigenvector indices.According to Fig.3,the magnitudes of the eigenvalues of PCID2and DSS1in bound state are lower than that of the unbound state.The first five principal components (PC)account for 54.1,62.9,72,and 84.3%for bound PCID2,bound DSS1,apo-PCID2,and apo-DSS1,respectively.The first several eigenvalues,which are relative to concerted motions,decreased quickly in amplitude and reached a constrained number,indicating more localized fluctuations rather than global fluctuation.

The top two principal components (PC1and PC2)were selected as reaction coordinates with which to con-struct the free energy surfaces (Fig.4).The free ener-gies were obtained with the equation G=?kT ln(P (x ))+C with k,T and C being the Boltzmann constant,

the

Fig.3Comparison of eigenvalues plotted against the corresponding eigenvector indices obtained from the C αcovariance matrix constructed from the equilibrium phase of MD simulations for a PCID2and b

DSS1

Fig.4a –d Free energy surfaces (FES)along the first two principle components (PC1and PC2)dur-ing the last 300ns MD trajecto-ries.a Apo-PCID2,b bound PCID2,c Apo-DSS1,d bound DSS1

127 Page 4of 9J Mol Model (2015) 21:127

absolute temperature and constant,respectively;P(x)is prob-ability.In Fig.4,the lower free energies correspond to the large probability with deeper red color.This implies that the state of the protein with the deeper red color would be more stable.As shown in Fig.4,the populated regions of bound proteins are less than those of unbound proteins.For PCID2protein,three highly populated regions are centered near [(2.05nm,?0.95nm),(?1.95nm,?1.05nm)and (?0.05nm,1.35nm)]apo-PCID2,and two highly populated regions centered near [(0.05nm,0.04nm)and (?0.05nm,0.02nm)]bound PCID2on the PCA map.For DSS1protein,there are two highly populated regions centered near [(?0.98nm,1.0nm)and (0.98nm,?1.0nm)]apo-DSS1and one highly populated region centered near (0.05nm,

?0.05nm)bound DSS1on the PCA map.The PCA analysis indicated that the reason DSS1is more stable is that it is required to commit to binding.The information obtained from the PCA is in accordance with that from the RMSF and RMSD analysis and implicates a mechanism of folding and binding involving induced fit (of the IDP)as suggested by Rogers et al.[49].Dynamics of PCID2

The global dynamics of PCID2is determined by protein ’s native structure and dynamic interactions among its residues [48].We calculated the native tertiary contacts (Qf)of

PCID2

Fig.5a –c Kinetics fitting of Qb and Qf for bound PCID2and apo-PCID2.a Apo-PCID2,b bound PCID2,c complex

Table 1

Kinetics constants a

τ(ns)

A B Bound PCID2Qf 58.480.0660.848Qb 52.630.0860.307apo-PCID2

Qf 111.11

0.060

0.850

a

All curves are fitted by A exp(?t /τ)+

B

Fig.6a Probability differences of β-strand and helix of apo-PCID2and bound PCID2protein.b ,c Probability of secondary structure of each residue during the equilibrated MD simulation for apo-DSS1(b )and bound DSS1(c )

J Mol Model (2015) 21:127 Page 5of 9 127

in apo-PCID2and bound PCID2and the native binding con-tacts (Qb)of the PCID2-DSS1complex using VMD software (shown in Fig.S1).The evolution of averaged Qf and Qb is shown in Fig.5.Overall,the Qf and unbinding kinetics can be represented well by single-exponential functions [48].The fitted kinetic data are shown in Table 1.Kinetics analysis of bound PCID2shows that the unbinding half time and the tertiary unfolding half time are 52.63ns and 58.48ns,respec-tively.The tertiary unfolding half time of apo-PCID2is 111.11ns,which is larger than that of bound PCID2,indicat-ing that bound PCID2is less flexible than apo-PCID2.Secondary structure of apo-PCID2,apo-DSS1and their complex

To gain further information on the changing secondary struc-ture,we calculated the percentage of secondary structure of each residue during the equilibrated MD simulation using the program STRIDE [50].Figure 6a shows the probability dif-ferences of β-strand and helix of apo-PCID2and bound PCID2proteins.The percentage with which residue Pro266forms β-strand in bound PCID2is higher than in apo-PCID2.

The secondary structure of residues 264–266in bound PCID2may differ from that in apo-PCID2in some snapshot during the MD simulation.The different secondary structures of res-idues 264–266are shown in Fig.7a,b.Concerning the helices,the probabilities of formation of helix IV (residues 268–274),helix VII (residues 317–332)and helix VIII (residues 341–350)in bound PCID2are larger than those in apo-PCID2.Figure 7a,b also shows a broken helix (residue 343–346)in apo-PCID2and a whole helix (residues 341–350)in bound PCID2.Both β-strand and helix are well known as important secondary structures of proteins.This suggests that

some

Fig.7Secondary structure of a apo-PCID2,b bound PCID2,c apo-DSS1and d bound DSS1shown in ribbon

representation

Fig.8Decomposition of ΔG pro ?res on a per-residue basis into contribu-tions from van der Waals energy (vdw),the sum of electrostatic energy and polar solvation free energy (ele+pol),and the nonpolar (nonpol)part of solvation free energy for residues of a DSS1and b PCID2for which |ΔG pro ?res |≥3kcal mol ?1

Table 2The averaged value of native helical content during the equilibrated MD simulation indicating differences in secondary structure of PCID2in the bound and unbound states.The interacting surface is between helix VII of PCID2and helix of DSS1

Helix I

Helix II Helix III Helix IV Helix V Helix VI Helix VII Helix VIII Helix IX Apo-PCID20.6770.9810.9830.8860.9610.8290.8730.7970.996Bound PCID2

0.666

0.991

0.946

0.928

0.910

0.876

0.916

0.952

0.996

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secondary structures of bound PCID2and DSS1are more stable than those in the unbound state.

The crystallographic structure shows that PCID2pro-tein consists of nine helices.In order to evaluate the stability of each helix,the native helical content of every helix was calculated along the trajectories of the MD simulation.Table2shows the averaged fraction of native helical content for the last300ns of MD simulation.The fraction of native helical content for each helix was taken as the ratio of the length over which this residue formed helical structure to the total length of the helix.It is clear that the averaged fraction of native helical content of helix VIII of apo-PCID2is different from that of bound PCID2.This result is consistent with the results of the secondary structure analysis.

To obtain information on the secondary structure of DSS1,the STRIDE program was also used to analyze apo-DSS1and bound DSS1proteins.Figure6b,c shows the probabilities of secondary structure of each residue in the DSS1protein.Figure7c,d shows one snapshot in apo-DSS1or in bound DSS1.It is clear that the helix in bound DSS1is more stable than that in apo-DSS1. Residues38–50exist in coil secondary structure in apo-DSS1with larger probability compared with bound DSS1.This is consistent with the conclusion that the secondary structures of IDPs are inclined to be helix and coil in the unbound state[51].Binding between DSS1and PCID2may improve the stability of both helix and coil.Binding between DSS1and PCID2

To evaluate the binding mechanism between DSS1and PCID2,and to further understand why apo-PCID2is more flexible than bound PCID2from an energy viewpoint,the binding free energy was caluculated on a per residue basis using the molecular mechanics generalized Born surface area(MM-GBSA)method.Figure8depicts the decompo-sition ofΔG values on a per residue basis into contribu-tions from van der Waals energy,the sum of electrostatic energy and polar solvation free energy,and the non-polar contribution to solvation free energy for residues with |ΔG pro?res|≥3kcal mol?1.As shown in Fig.8,16residues of DSS1and14residues of PCID2play key roles in the interaction of DSS1with PCID2.The positions of key residues in the complex are shown in Fig.9a.It is clear that the key residues are located at the surface of the binding site.

Secondary structure analysis showed that helix VIII is more stable in the bound state than in the unbound state.As shown in Fig.1,the helix of DSS1is close to helix VIII of PCID2. According to the interaction energy,there are seven residues with large van der Waals contribution in the binding site be-tween the helix of DSS1and helix VIII of PCID2.As shown in Fig.9b,the interacting residues between the helix of DSS1 and helix VIII of PCID2are hydrophobic.Residue Tyr65also contributes large electrostatic energy,and this residue forms a stable hydrogen bond with Asp341of PCID2.However, Tyr65also contributes to the hydrophobic core with its

side Fig.9a Position of key residues in the complex.The key residues are

shown in ball representation,and labeled.b Interaction surface between

helix VIII of PCID2and the helix of DSS1are shown in hydrophobic

surface.The key residues in PCID2are shown in ball and stick

representation,as well as stick representation in DSS1.The helices are

shown in ribbon representation.c DSS1is shown in hydrophobic surface

and stick representation.Key residues are shown in ball and stick

representation

J Mol Model (2015) 21:127 Page7of9 127

chain.This means that the hydrophobic core is formed by three residues(Ala342,Val345and Phe349)of PCID2and four residues(Leu56,Glu59,Leu60and Tyr65)of DSS1.A hydrogen bond outside the core might increase the stability of the hydrophobic core.It is well know that the hydrophobic core plays an important role in protein–protein interactions [52],thus the reason that helix VIII is more stable in the bound than in the unbound state is the hydrophobic interaction in bound PCID2.

As shown in Fig.9c,more hydrophilic residues were found;this is in accordance with the nature of IDP proteins, which consist of more hydrophilic residues.The secondary structure of residues(41–46)of DSS1in the bound state differ from that in the unbound state(Fig.7c,d).The energy terms of residues(41–46)of DSS1show large electrostatic energy, especially residues43–46.

Conclusion

We have performed three independent MD simulations for apo-PCID2,apo-DSS1and the PCID2–DSS1complex to study the stability of PCID2in the bound/unbound state and the interdependence of binding in the PCID2–DSS1complex. The results revealed that apo-DSS1is highly flexible,and that apo-PCID2is unstable,especially in helices IV and VIII of apo-PCID2.When the helix of DSS1binds in the cleft be-tween the helices VII and VIII of PCID2,helix VIII and the helix of DSS1are stabilized,causing DSS1to coil into a more regular secondary structure.The interaction energies suggest that seven residues make a large van der Waals contribution to the binding between the helix of DSS1and helix VIII of PCID2,and a hydrophobic core is formed between the helix of DSS1and helix VIII of PCID2.These results are in good agreement with experimental observations.The MD simula-tions indicate that DSS1affects the stability of PCID2,making it more stable.These results will be helpful in understanding the interaction between DSS1and PCID2,and provide signif-icant insight into the function of the TREX-2complex in coupling transcription and processing with mRNA export.

Acknowledgments This work was partially supported by funding from the National Natural Science Foundation of China(61271378and 11447004),the Natural Science Foundation of Shandong Province (ZR2014JL006and ZR2012CL09)and A Project of Shandong Province Higher Educational Science and Technology Program(J14LJ05). Conflict of interest The authors declare that they have no conflict of interest.References

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歌舞剧 猫 中英对照歌词

Are you blind when you're born? Can you see in the dark? 你出生时是目盲的吗?你能在黑暗处看到事物吗? Dare you look at a king? Would you sit on his throne? 你敢目室国王吗?你想坐在王位上吗? Can you say of your bite that it's worse than your bark? 你能说你的咬力不如你的叫声吗? Are you cock of the walk when you're walking alone? 当你独自行走时你很自信自傲吗? Because jellicles are and jellicles do 因为杰利克是杰利克能 Jellicles do and jellicles would 杰利克能杰利克会 Jellicles would and jellicles can 杰利克会杰利克能 Jellicles can and jellicles do 杰利克能杰利克做 When you fall on your head, do you land on your feet? 当你头朝下落下时,你能用脚着地吗? Are you tense when you sense there's a storm in the air? 当你感到风暴来临时,你会很紧张吗? Can you find your way blind when you're lost in the street? 当你迷路时,你能本能的找到正确的方向吗? Do you know how to go to the heaviside layer? 你知道如何升向九重天吗? Because jellicles can and jellicles do 因为杰利克能杰利克做 Jellicles do and jellicles can 杰利克做杰利克能 Jellicles can and jellicles do 杰利克能杰利克做 Jellicles do and jellicles can 杰利克做杰利克能 Jellicles can and jellicles do 杰利克能杰利克做 Can you ride on a broomstick to places far distant? 你能骑着扫把去很远的地方吗? Familiar with candle, with book, and with bell? 你喜爱玩耍蜡烛,书籍或是铃铛吗? Were you Whittington's friend? The Pied Piper's assistant? 你是惠廷顿的朋友?或是吹笛手的助理吗? Have you been an alumnus of heaven and hell? 你能自由的通往天堂和地狱吗? Are you mean like a minx? Are you lean like a lynx? 你是一个爱出风头的姑娘吗?你瘦的像一只山猫吗? Are you keen to be seen when you're smelling a rat? 当你闻到一只老鼠你会努力的寻找吗? Were you there when the pharaoh commissioned the Sphinx? 当法老委派做狮身人面像时你在场吗? If you were, and you are, you're a jellicle cat 如果你在并且你是,你是一只杰利克猫. Jellicle songs for jellicle cats 杰利克歌咏杰利克猫 Jellicle songs for jellicle cats 杰利克歌咏杰利克猫 Jellicle songs for jellicle cats 杰利克歌咏杰利克猫

歌词

我的歌声里 没有一点点防备 也没有一丝顾虑 你就这样出现 在我的世界里带给我惊喜情不自己可是你偏又这样 在我不知不觉中悄悄地消失 从我的世界里没有音讯 剩下的只是回忆 你存在我深深的脑海里 我的梦里我的心里我的歌声里 你存在我深深的脑海里 我的梦里我的心里我的歌声里 还记得我们曾经 肩并肩一起走过那段繁花巷口 尽管你我是陌生人是过路人 但彼此还是感觉到了 对方的一个眼神一个心跳 一种意想不到的快乐 好像是一场梦境命中注定 你存在我深深的脑海里 我的梦里我的心里我的歌声里 你存在我深深的脑海里 我的梦里我的心里我的歌声里 世界之大为何我们相遇 难道是缘分难道是天意 你存在我深深的脑海里 我的梦里我的心里我的歌声里 你存在我深深的脑海里 我的梦里我的心里我的歌声里 你存在我深深的脑海里 我的梦里我的心里我的歌声里 如水 期待过我们似细水 可惜蒸发出眼泪 明白你最近有些暂时伴侣偷一刻午睡彷佛专一使你极空虚 怀疑被你抱着我念着谁 无论你再好亦舍得失去 难过亦过难道我 嫌损失未够多

早放手可减轻痛楚 不等泡沫给吹破 不想去知谁填补我 无悔在我还是我 任你多么差错 无谓去追问为何 深知告别损失非我 让情人离别 似水清洗我 原谅你对着我说谎 出于好意的作状 明白你最近已经避谈近况 早不敢寄望 心中早把相爱如观光 情如瀑布泻下也未惊慌 心境已随着那水花得到释放 难过亦过难道我 嫌损失未够多 早放手可减轻痛楚 不等泡沫给吹破 不想去知谁填补我 无悔在我还是我 任你多么差错 无谓去追问为何 深知告别损失非我 让情人离别 似水清洗我 难过亦过难道我 嫌损失未够多 早放手可减轻痛楚 不等泡沫给吹破 不想去知谁填补我 无悔在我还是我 任你多么差错 无谓去追问为何 深知告别损失非我 让情人离别 似水清洗我 心中有涟漪吹过又回到最初平静去做我

英语文化 学英语必须要知道的经典英文歌曲14 Hallelujah

歌曲背景 "Hallelujah" is a song written by Canadian singer Leonard Cohen, originally released on his album Various Positions (1984). Achieving little initial success, the song found greater popular acclaim through a recording by John Cale, which inspired a recording by Jeff Buckley. It has been viewed as a "baseline" for secular hymns. "Hallelujah"为加拿大著名游吟诗人、民谣歌手Leonard Cohen在1985年创作的歌曲,收录在其专辑"Various Positions"中。其歌词充满诗意,内涵丰富,曲调缓慢忧伤,加上Leonard沧桑嗓音的低吟浅唱,演绎出了一种清淡而悠长的回味。 Hallelujah的版本很多,其中最有影响力的还是美国著名创作型歌手Jeff Buckley的翻唱版本,被收录在其1994年的专辑"Grace"中。Jeff被U2的Bono形容为“噪海中的纯净一滴”,他的声音明丽甜蜜又性感飘渺,诠释起悲伤和记忆来却更令人印象深刻。 中国歌手邓紫棋在现场演唱会上翻唱了本曲。 英文歌词 Now I've heard there was a secret chord 我曾听闻一曲传奇中的旋律 That David played, and it pleased the Lord 是大卫弹奏来取悦上帝的赞颂 But You don't really care for music, do You? 但祢真正喜悦的(是人的作为,而)不是音乐,对吧? Well it goes like this 旋律是这样的 The fourth, the fifth F和弦,G和弦(复杂的心情无可言喻) The minor fall, the major lift 大小调起承转合(指戴维泣不成声的祷告颂唱,至五音不全) The baffled king composing Hallelujah

英文典范歌谣一起唱1A1B1C歌词

1A 1.Are You Sleeping? Are you sleeping? Are you sleeping? Brother John, Brother John? Morning bells are ringing, Morning bells are ringing. Ding, ding, dong! Ding, ding, dong! 2.Ten Little Indians One little, two little, three little Indians,

Four little, five little, six little Indians, Seven little, Eight little, Nine little Indians, Ten little Indian boys. One little, two little, three little Indians, Four little, five little, six little Indians, Seven little, Eight little, Nine little Indians, Ten little Indian girls. 3.Happy Birthday to You Happy birthday to you. Happy birthday to you. Happy birthday, dear friend. Happy birthday to you.

4.Hot Potato One potato, two potatoes, Three potatoes, four, Five potato, six potatoes, Seven potatoes, more. 5.Hot Cross Buns Hot cross buns! Hot cross buns! One a penny, two a penny. Hot cross buns! If you have no daughters, Give them to you sons!

English song-as long as you love me英文经典脍炙人口歌曲歌词解析

歌名:As Long As You Love Me 歌手:Justin Bieber 所属专辑:Believe Acoustic 作曲 : Persson Svensson 作词 : Persson Svensson As long as you love me yeah 只要你爱我就好 I'm under pressure, seven billion people in the world trying to fit in 我们在压力下跟着全世界70亿人适应这个社会 Keep it together, smile on your face even though your heart is frowning 紧紧相依,你心有困懑却面带笑容 But hey now, you know girl, we both know it's a cruel world 但是现在,宝贝你知道,我们都知道世界多么残酷 But I will take my chances 但我愿意(搏一搏)抓住我的机会 As long as you love me, we could be starving, 只要你爱我,我们可以挨饿(饥肠辘辘) We could be homeless, we could be broke 可以流离失所,也可以支离破碎 As long as you love me I'll be your platinum, I'll be your silver, i'll be your gold 只要你爱我,我是你的铂金,我是你的银,我是你的财富(我会不离不弃,无坚不摧,所向披靡)

英文歌词

1、《Mister Sun》 Oh Mister Sun, Sun, Mister Golden Sun, Please shine down on me. Oh Mister Sun, Sun,Mister Golden Sun, Hiding behind a tree… These little children , Are asking you To please come out So we can play with you. Oh Mister Sun, Sun,Mister Golden Sun, Please shine down on me! Oh Mister Sun, Sun, Mister Golden Sun, Please shine down on me. Oh Mister Sun, Sun, Mister Golden Sun,Hiding behind a tree…These little children Are asking youTo please come out So we can play with you. Oh Mister Sun, Sun,Mister Golden Sun, Please shine down on,Please shine down on, Please shine down on me! 2、Mango Walk My brother did a tell me That you go mango walk You go mango walk(2×) My brother did a tell me That you go mango walk And pick all the numbe r ?leven 3、Mosquito Mosquito one, Mosquito two. Mosquito jump in the old man ,shoe Zzzzzzzz(clap the mosquito ) 4、Artist:harrybelafonte Songs Title:coconut woman (Coconuts, coconuts) (Coconuts, coconuts) Coconut woman is calling out And everyday you can hear her shout Coconut woman is calling out And everyday you can hear her shout Get your coconut water (Four for five) Man, it's good for your daughter (Four for five) Coco got a lotta iron (Four for five) Make you strong like a lion (Four for five) A lady tell me the other day No one can take her sweet man away I ask her what was the mystery She say coconut water and rice curry You can cook it in a pot (Four for five) You can serve it very hot (Four for five) Coco got a lotta iron (Four for five) Make you strong like a lion (Coconuts, coconuts) Coconut woman says you'll agree Coconut make very nice candy The thing that's best If you're feeling glum Is coconut water with a little rum It could make you very tipsy (Four for five) Make you feel like a gypsy (Four for five) Coco got a lotta iron (Four for five) Make you strong like a lion (Four for five) Ah, play that thing Coconut woman is calling out And everyday you can hear her shout Coconut woman is calling out And everyday you can hear her shout Get your coconut water (Four for five) Man, it's good for your daughter (Four for five) Get your coconut candy (Four for five) Make you feel very dandy (Four for five) Coco, coco, coco... Coconut, coconut Coconut, coconut... -

听的圣诞节英语歌曲

听的圣诞节英语歌曲 下面是一些圣诞节英文歌曲推荐! 1、Everybody Knows I Love U 圣诞表白 2、Hallelujah-Alexandra Burke圣诞单曲销售冠军 3、圣诞必听英文歌曲John Lennon(Happy Christmas) 4、豌豆公主Kylie Minogue圣诞情调Santa Baby 5、小天后Taylor Swift演绎缤纷圣诞Last Christmas 6、NIKE最新圣诞广告歌曲完整版 7、Lady GaGa 欢乐圣诞单曲Christmas Tree 8、最畅销圣诞歌Mariah Carey(All I Want For Christmas Is You) 9、超人气童星Justin Bieber在奥巴马总统面前献唱圣诞歌曲 10、可爱童声贺圣诞When Christmas comes to town 欢乐合唱团相约快乐圣诞 Glee Cast - Last Christmas 美国福克斯电视台于2009年推出的热门青春音乐剧《欢乐合唱团》Glee盛邀剧中的男女主演们,包括Lea Michele, Amber Riley, Cory Monteith, Kevin McHale, Jenna Ushkowitz, Chris Colfer, Dianna Agron, Mark Salling等一席欢乐合唱团的团员们齐齐出动,为我们带来了这首欢快的经典翻唱"Last Christmas"。 绯闻女孩Queen B喊你回家过圣诞 Leighton Meester - Christmas "Christmas (Baby Please Come Home)"是Darlene Love于1963年发表的经典圣诞歌曲,后被乐队U2、乐坛天后Mariah Carey翻唱。

hallelujah英文歌词

I've heard there was a secret chord That David played, and it pleased the Lord But you don't really care for music, do you? It goes like this The fourth, the fifth The minor fall, the major lift The baffled king composing Hallelujah Hallelujah, Hallelujah Hallelujah, Hallelujah Your faith was strong but you needed proof You saw her bathing on the roof Her beauty in the moonlight overthrew you She tied you to a kitchen chair She broke your throne, and she cut your hair And from your lips she drew the Hallelujah Hallelujah, Hallelujah Hallelujah, Hallelujah Baby I have been here before I know this room, I've walked this floor I used to live alone before I knew you. I've seen your flag on the marble arch Love is not a victory march It's a cold and it's a broken Hallelujah Hallelujah, Hallelujah Hallelujah, Hallelujah Maybe there’s a God above But all I’ve ever learned from love Was how to shoot at someone who outdrew you It’s not a cry you can hear at night It’s not somebody who has seen the light It’s a cold and it’s a broken Hallelujah Hallelujah, Hallelujah Hallelujah, Hallelujah I did my best, it wasn't much I couldn't feel, so I tried to touch I've told the truth, I didn't come to fool you And even though it all went wrong I'll stand before the Lord of Song With nothing on my tongue but Hallelujah

英文歌歌词

Miley Cyrus - The Climb / 麦莉·赛勒斯- 攀登 I can almost see it / 眼前依稀浮现 That dream I'm dreamin' but / 萦绕心头的那个梦境There's a voice inside my head saying / 脑海里却响起一个声音 you'll never reach it / 你永远也不会到达彼岸Every step I'm taking / 我迈出的每一步 Every move I make feels /我做过的每件事 Lost with no direction / 无不使我迷失方向 My faith is shakin / 开始动摇的,是我的信念 But I, I gotta keep tryin. / 可我,我还是要继续求索Gotta keep my head held high / 还是要挺胸抬头、阔步前行 There's always gonna be another mountain / 总会有下一座山峦 I'm always gonna wanna make it move / 在等我去将它移开 Always gonna be an uphill battle / 总会有下一个山坡 Sometimes I'm gonna have to lose / 很可能令我无法越过 Ain't about how fast I get there / 不在于我要用多久才能抵达峰顶 Ain't about what's waitin on the other side / 不在于山那边倒底是怎样的风景 It's the climb / 这就是攀登 The struggles I'm facing / 我面对的每次搏击 The chances I'm taking / 我抓住的每次机遇Sometimes might knock me down but / 有时会令我一败涂地 No I'm not breaking / 却决不会磨去我的意志 I may not know it / 或许我不懂其中的意义 But these are the moments that / 但这些时刻却会成为 I'm gonna remember most, yeah / 我一辈子可以珍藏的回忆,啊 Just gotta keep going / 只管继续前进 And I, I gotta be strong / 我要,我要变得坚强 Just keep pushing on 'cause / 只须奋力前行,因为 There's always gonna be another mountain / 总会有下一座山峦I'm always gonna wanna make it move / 在等我去将它移开 Always gonna be an uphill battle / 总会有下一个山坡 Sometimes I'm gonna have to lose / 很可能令我无法越过 Ain't about how fast I get there / 不在于我要用多久才能抵达顶峰 Ain't about what's waitin on the other side / 不在于山那边倒底是怎样的风景 It's the climb / 这就是攀登 Yeah-yeah / 啊- There's always gonna be another mountain / 总会有下一座山峦 I'm always gonna wanna make it move / 在等我去将它移开 Always gonna be an uphill battle / 总会有下一个山坡 Sometimes you're gonna have to lose / 很可能令我无法越过 Ain't about how fast I get there / 不在于我要用多久才能抵达顶峰 Ain't about what's waitin on the other side / 不在于山那边倒底是怎样的风景 It's the climb / 这就是攀登 Yeah-yeah-yeah / 啊- - Keep on moving / 继续前行 Keep climbing / 继续攀登 Keep the faith / 坚守信念 Baby / 宝贝 It's all about / 这一切就是 It's all about the climb / 这一切就是攀登

Alexandra Burke - Hallelujah

Hallelujah Well I heard there was a secret chord 我听说有个神秘的和弦 That David played, and it pleased the Lord 大卫弹奏以取悦主 But you don't really care for music, do ya? 可你并不关心音乐,不是么 Well it goes like this 它这样奏起 The fourth, the fifth 四度,五度(2)

The minor fall and the major lift 小调降,大调升The baffled king composing Hallelujah 徒然哀求的君王谱下哈利路亚(3) Hallelujah Hallelujah 哈利路亚哈利路亚 Hallelujah Hallelujah 哈利路亚哈利路亚Well Your faith was strong but you needed proof 你信心坚定但需受考验 You saw her bathing on the roof 你在屋顶见她沐浴 Her beauty and the moonlight overthrew you 她在月光下的美丽将你击溃(4) She tied you to her kitchen chair 她将你捆在厨房的椅上 And she broke your throne and she cut your hair 她毁了你的王位剪下你的头发(5) And from your lips she drew the Hallelujah 从你的唇中她吸吮哈利路亚 Hallelujah Hallelujah 哈利路亚哈利路亚 Hallelujah Hallelujah 哈利路亚哈利路亚

Rufus Wainwright - Hallelujah中英文歌词对照(伤感抒情英文)

Rufus Wainwright - Hallelujah 歌词翻译: I heard there was a secret chord that David played and it pleased the Lord But you don’t really care for music, do you? Well it goes like this : The fourth, the fifth, the minor fall and the major lift The baffled king composing Hallelujah 我听见了那神秘悠扬的旋律 那是以色列王(David)为取悦上帝而奏 但也许你并不在意旋律本身,不是吗? 音乐却是这样起来的 第4,第5,小调落下,大调升起 饱受煎熬的国王写下了赞美之歌-哈利路亚 Hallelujah Hallelujah Hallelujah Hallelujah… 哈利路亚,哈利路亚,哈利路亚““` Your faith was strong but you needed proof You saw her bathing on the roof Her beauty and the moonlight overthrew you And she tied you to her kitchen chair She broke your throne and she cut your hair But from your lips she drew the Hallelujah 你信念坚定却也要受到考验 你在屋顶上看到她在那里沐浴 她的美貌在月光下就已经把你征服 她会把你骗到坐上厨房里的椅子上 推翻你的宝座,并剪下你的发丝 为了听到你的唇边的赞美之歌-哈利路亚 Hallelujah Hallelujah Hallelujah Hallelujah… 哈利路亚,哈利路亚,哈利路亚“““` Baby I’ve been here before I’ve seen this room and I’ve walked this floor I used to live alone before I knew ya And I’ve seen your flag on the marble arch

70首唯美欧美歌推荐

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