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1.
Topologically, platelet factor-4 kinocidins consist of distinct N-terminal extended, C-terminal helical, and interposing gamma-core structural domains. The C-terminal alpha-helices autonomously confer direct microbicidal activity, and the synthetic antimicrobial peptide RP-1 is modeled upon these domains. In this study, the structure of RP-1 was assessed using several complementary techniques. The high-resolution structure of RP-1 was determined by NMR in anionic sodium dodecyl sulfate (SDS) and zwitterionic dodecylphosphocholine (DPC) micelles, which approximate prokaryotic and eukaryotic membranes, respectively. NMR data indicate the peptide assumes an amphipathic alpha-helical backbone conformation in both micelle environments. However, small differences were observed in the side-chain orientations of lysine, tyrosine, and phenylalanine residues in SDS versus DPC environments. NMR experiments with a paramagnetic probe indicated differences in positioning of the peptide within the two micelle types. Molecular dynamics (MD) simulations of the peptide in both micelle types were also performed to add insight into the peptide/micelle interactions and to assess the validity of this technique to predict the structure of peptides in complex with micelles. MD independently predicted RP-1 to interact only peripherally with the DPC micelle, leaving its spherical shape intact. In contrast, RP-1 entered deeply into and significantly distorted the SDS micelle. Overall, the experimental and MD results support a preferential specificity of RP-1 for anionic membranes over zwitterionic membranes. This specificity likely derives from differences in RP-1 interaction with distinct lipid systems, including subtle differences in side chain orientations, rather than gross changes in RP-1 structure in the two lipid environments.  相似文献   

2.
Problems with transdermal drug delivery were directly associated with the skin barrier which is the lipid bilayer at the stratum corneum. Chemical penetration enhancers such as swollen micelles that formed from the solubilisation of the surfactants in the nano-emulsion system could provide an effective solution. However, the structural properties of swollen micelles from nano-emulsions of palm-oil esters, whose behaviour is related to colloidal systems, have not been studied in great detail. In this paper, we report on the use of molecular dynamics (MD) simulations to investigate the structural properties of swollen micelles of oleyl oleate (OE). Five series of 10 ns MD simulations were performed at different micelle compositions to determine the structural evolution of OE/Span20 (S20) swollen micelles. We also carried out four MD simulations on the structure of S20, OE/S20, Tween80 (T80) and OE/T80 micelles to study the effect of different surfactants and the addition of OE into the systems. The shapes of the swollen micelles were observed to vary by the difference in the micelle composition, the surfactants used and the addition of OE. The results were correlated with published theory, and consistent with experimental results on the phase behaviour of the nano-emulsion system.  相似文献   

3.
Gao X  Wong TC 《Biopolymers》2001,58(7):643-659
Adrenocorticotropin (ACTH) (1-10), an adrenocorticotropin hormone fragment, has been studied by molecular dynamics (MD) simulation in an NPT ensemble in an explicit dodecylphosphocholine (DPC) micelle. Two starting configurations of the peptide/micelle system, corresponding to the insertion and surface-binding modes, were used. A common equilibrated configuration, in which the peptide lies parallel to the micellar surface, was reached from both simulations. In the initial part of the simulations, distance restraints derived from NMR nuclear Overhauser enhancements were incorporated before the peptide reached an equilibrium configuration with respect to the micelle. Analyses of the trajectories from the subsequent free (unrestrained) MD simulation showed that ACTH (1-10) does not conform strictly to a helical structure. The loss of the helical structure is due to decreased intramolecular hydrogen bonding accompanied by an increase of hydrogen bonding between the amide protons of the peptide and the micellar head groups. However, the extent of the latter interaction is less pronounced than in the negatively charged SDS micelle. The final structure enhances the amphipathic nature of the peptide, facilitating better interactions at the water-hydrophobic interface. The primary hydrophobic interactions with the micelle came from the side chains of Met4, Phe7, and Trp9. All peptide bonds were either hydrated or were involved in intramolecular hydrogen bonding. The interactions with the DPC micelle, the conformation of the bound peptide, and the dynamics of the peptide, as revealed by the time correlation functions of the N-H bonds, were compared with those of the ACTH (1-10)/SDS system studied previously by MD simulations.  相似文献   

4.
The structure and interactions of the 1-24 fragment of the adrenocorticotropin hormone, ACTH (1-24), with membrane have been studied by molecular dynamics (MD) simulation in an NPT ensembles in two explicit membrane mimics, a dodecylphosphocholine (DPC) micelle and a dimyristoylphosphatidylcholine (DMPC) bilayer. The starting configuration of the peptide/lipid systems had the 1-10 segment of the peptide lying on the surface of the model membrane, the same as the equilibrated structure (by MD) of ACTH (1-10) in a DPC micelle. The simulations showed that the peptide adopts the surface-binding mode and essentially the same structure in both systems. Thus the results of this work lend support to the assumption that micelles are reasonable mimics for biological membranes for the study of peptide binding. The 1-10 segment is slightly tilted from the parallel orientation to the interface and interacts strongly with the membrane surface while the more polar 11-24 segment shows little tendency to interact with the membrane surface, preferring to reside primarily in the aqueous phase. Furthermore, the 1-10 segment of the peptide binds to the DPC micelle in essentially the same way as ACTH (1-10). Thus the MD results are in excellent agreement with the model of interaction of ACTH (1-24) with membrane derived from NMR experiments. The secondary structure and the hydration of the peptide and the interactions of specific residues with the lipid head groups have also been analyzed.  相似文献   

5.
Abstract

The structure and interactions of the 1–24 fragment of the adrenocorticotropin hormone, ACTH (1–24), with membrane have been studied by molecular dynamics (MD) simulation in an NPT ensembles in two explicit membrane mimics, a dodecylphosphocholine (DPC) micelle and a dimyristoylphosphatidylcholine (DMPC) bilayer. The starting configuration of the peptide/lipid systems had the 1–10 segment of the peptide lying on the surface of the model membrane, the same as the equilibrated structure (by MD) of ACTH (1–10) in a DPC micelle. The simulations showed that the peptide adopts the surface-binding mode and essentially the same structure in both systems. Thus the results of this work lend support to the assumption that micelles are reasonable mimics for biological membranes for the study of peptide binding. The 1–10 segment is slightly tilted from the parallel orientation to the interface and interacts strongly with the membrane surface while the more polar 11–24 segment shows little tendency to interact with the membrane surface, preferring to reside primarily in the aqueous phase. Furthermore, the 1–10 segment of the peptide binds to the DPC micelle in essentially the same way as ACTH (1–10). Thus the MD results are in excellent agreement with the model of interaction of ACTH (1–24) with membrane derived from NMR experiments. The secondary structure and the hydration of the peptide and the interactions of specific residues with the lipid head groups have also been analyzed.  相似文献   

6.
ACTH (1-10), an adrenocorticotropin hormone fragment, was studied by molecular dynamics (MD) simulation in the NPT ensemble in an explicit sodium dodecylsulfate (SDS) micelle. Initially, distance restraints derived from NMR nuclear Overhauser enhancements were incorporated during the equilibration stage of the simulation. The analyses of the trajectories from the subsequent unrestrained MD showed that ACTH (1-10) does not conform to a helical structure at the micelle-water interface; however, the structure is amphipathic. The loss of the helical structure is due to decreased intramolecular hydrogen bonding accompanied by an increase of hydrogen bonding between the amide hydrogens of the peptide and the micelle head-groups. ACTH (1-10) was found to lie on the surface of the SDS micelle. Most of the hydrophobic interactions came from the side-chains of Met-4, Phe-7 and Trp-9. The peptide bonds were either hydrated or involved in intramolecular hydrogen bonding. Decreased hydration for the backbone of His-6 and Phe-7 was due to intermolecular hydrogen bonding with the SDS head-groups. The time correlation functions of the N-H bonds of the peptide in water and in the micelle showed that the motions of the peptide, except for the N- and C-termini, are significantly reduced when partitioned in the micelle.  相似文献   

7.
A peptide fragment from a protein hairpin turn region was modified by addition of isoleucine residues to both ends to enhance binding to lipid micelles; the resulting peptide (I(1)-I(2)-C(3)-N(4)-N(5)-P(6)-H(7)-I(8)-I(9)) contains the core sequence I-C-N-N-P-H from an antibody-binding region of hemagglutinin A. Nuclear magnetic resonance (NMR) diffusion measurements indicated partial binding (43-65%) of the peptide to micelles of n-octylglucoside and significantly stronger binding (85%) to dodecylphosphocholine (DPC) micelles. Simulated annealing and conformational analysis using nuclear Overhauser enhancement restraints revealed a type I or III hairpin turn between residues N(5) and I(8) of the DPC-bound peptide. Amide exchange experiments support the possibility that a hydrogen bond forms between N(5) and I(8), stabilizing the turn. In contrast, no discernable structure was observed for the peptide in aqueous solution by either NMR or circular dichroism. Molecular dynamics simulations of DPC micelles and peptide-micelle complexes suggested that the peptide lies flat on the micelle surface and showed rapid rearrangement of the lipids to accommodate the bound peptide. According to a search performed using the basic local alignment search tool (BLAST), the sequences N-P-H-I and N-P-H-V are present as hairpin turns in eight of the nine proteins whose crystal structures were available. The addition of isoleucine residues and the use of lipid micelles to stabilize hairpin conformations equivalent to those found in proteins generates new possibilities for reproducing biologically important hairpin turns from short, linear peptides.  相似文献   

8.
The ubiquitin associated domain of p62 is a small three-helix bundle of approximately 50 residues that mediates the recognition of polyubiquitin chains and ubiquitylated substrates. The solution structure of a 52 residue construct containing this domain has been characterized using heteronuclear nuclear magnetic resonance (NMR) methods. The resulting ensemble of NMR-derived structures was used in molecular dynamics (MD) simulations to investigate the equilibrium conformation and dynamics of this domain. NOE and (15)N relaxation data have been used to validate the structural ensemble produced by the MD simulations and show a good correlation for residues in regions of secondary structure. A similar approach was taken using an ensemble of structures from the MD simulations to calculate electronic circular dichroism (CD) and IR spectra from first principles with an encouraging correlation with the experimental CD and IR data.  相似文献   

9.
《Biophysical journal》2019,116(9):1682-1691
The dynamics of phosphocholine and maltoside micelles, detergents frequently used for membrane protein structure determination, were investigated using electron paramagnetic resonance of spin probes doped into the micelles. Specifically, phosphocholines are frequently used detergents in NMR studies, and maltosides are frequently used in x-ray crystallography structure determination. Beyond the structural and electrostatic differences, this study aimed to determine whether there are differences in the local chain dynamics (i.e., fluidity). The nitroxide probe rotational dynamics in longer chain detergents is more restricted than in shorter chain detergents, and maltoside micelles are more restricted than phosphocholine micelles. Furthermore, the micelle microviscosity can be modulated with mixtures, as demonstrated with mixtures of 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate with n-dodecylphosphocholine, n-tetradecylphosphocholine, n-decyl-β-D-maltoside, or n-dodecyl-β-D-maltoside. These results indicate that observed differences in membrane protein stability in these detergents could be due to fluidity in addition to the already determined structural differences.  相似文献   

10.
To assess the accuracy of the molecular dynamics (MD) models of nucleic acids, a detailed comparison between MD-calculated and NMR-observed indices of the dynamical structure of DNA in solution has been carried out. The specific focus of our comparison is the oligonucleotide duplex, d(CGCGAATTCGCG)(2), for which considerable structural data have been obtained from crystallography and NMR spectroscopy. An MD model for the structure of d(CGCGAATTCGCG)(2) in solution, based on the AMBER force field, has been extended with a 14 ns trajectory. New NMR data for this sequence have been obtained in order to allow a detailed and critical comparison between the calculated and observed parameters. Observable two-dimensional (2D) nuclear Overhauser effect spectroscopy (NOESY) volumes and scalar coupling constants were back-calculated from the MD trajectory and compared with the corresponding NMR data. The comparison of these results indicate that the MD model is in generally good agreement with the NMR data, and shows closer accord with experiment than back-calculations based on the crystal structure of d(CGCGAATTCGCG)(2) or the canonical A or B forms of the sequence. The NMR parameters are not particularly sensitive to the known deficiency in the AMBER MD model, which is a tendency toward undertwisting of the double helix when the parm.94 force field is used. The MD results are also compared with a new determination of the solution structure of d(CGCGAATTCGCG)(2) using NMR dipolar coupling data.  相似文献   

11.
Pol peptide, an oligopeptide corresponding to the 27 C-terminal amino acids of DNA polymerase from herpes simplex virus type 1, has recently been suggested to translocate from endosomal compartments into the cytosol after being intracellularly delivered via a protein carrier. While an acidic environment was thought to be important for Pol peptide membrane translocation, the mechanism of translocation remains unclear. To investigate the influence of an acidic environment on the conformational properties of the peptide and on its propensity to interact with lipid bilayers, we characterized the structure of Pol peptide at different pH values by both circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. The influence of detergent micelles, which mimic biological lipid membranes, on the peptide secondary structure was also studied. Our CD results indicate that the peptide is in a random conformation in aqueous solution at both acidic and basic pH, whereas in the presence of dodecylphosphocholine (DPC) micelles, it assumes a partial alpha-helical structure which is significantly pH-dependent. An NMR study confirmed that, in the presence of DPC micelles, a short C-terminal alpha-helix is present at pH 6.5, whereas almost two-thirds of the peptide (residues 10-26) fold into an extended amphipathic alpha-helix at pH 4.0. The orientation of Pol peptide relative to the DPC micelle was investigated using paramagnetic probes at both pH 4.0 and 6.5. These studies show that the peptide inserts deeply into the micelle at pH 4.0, whereas it is more exposed to the aqueous environment at pH 6.5. On the basis of these results, a model which might explain the mechanism of translocation of Pol peptide from acidic endosomes to the cytosol is discussed.  相似文献   

12.
The Bcl-2 family of proteins play a pivotal role in the regulation of programmed cell death. One of the postulated mechanisms for the function of these proteins involves the formation of ion channels in membranes. As a first step to structurally characterize these proteins in a membrane environment, we investigated the structure of a Bcl-x(L) mutant protein when incorporated into small detergent micelles. This form of Bcl-x(L) lacks the loop (residues 49-88) between helix 1 and helix 2 and the putative C-terminal transmembrane helix (residues 214-237). Below the critical micelle concentration (CMC), Bcl-x(L) binds detergents in the hydrophobic groove that binds to pro-apoptotic proteins. However, above the CMC, Bcl-x(L) undergoes a dramatic conformational change. Using NMR methods, we characterized the secondary structure of Bcl-x(L) in the micelle-bound form. Like Bcl-x(L) in aqueous solution, the structure of the protein when dissolved in dodecylphosphocholine (DPC) micelles consists of several alpha-helices separated by loops. However, the length and position of the individual helices of Bcl-x(L) in micelles differ from those in aqueous solution. The location of Bcl-x(L) within the micelle was examined from the analysis of protein-detergent NOEs and limited proteolysis. In addition, the mobility of the micelle-bound form of Bcl-x(L) was investigated from NMR relaxation measurements. On the basis of these studies, a model is proposed for the structure, dynamics, and location of Bcl-x(L) in micelles. In this model, Bcl-x(L) has a loosely packed, dynamic structure in micelles, with helices 1 and 6 and possibly helix 5 partially buried in the hydrophobic interior of the micelle. Other parts of the protein are located near the surface or on the outside of the micelle.  相似文献   

13.
Mixed micelles of deoxycholate (DOC) and 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) have been prepared in which the POPC was specifically deuterated in the 2-, 6-, 10-, or 16-position of the palmitoyl chain or in the N-methyl position of the choline head group. The deuterium nuclear magnetic resonance (2H NMR) spectrum of each of these specifically deuterated mixed micelles consists of a singlet whose line width depends upon the position of deuteration. Spin-spin relaxation times indicate a gradient of mobility along the POPC palmitoyl chain in the mixed micelle, with a large increase in mobility on going from the 10- to the 16-position. Spin-lattice relaxation times (T1's) demonstrate a similar gradient of mobility. Both trends in NMR relaxation behavior are consistent with a bilayer arrangement for the solubilized POPC. 2H T1 times for DOC/POPC micelles are significantly shorter than those measured in other bilayer systems, indicating unusually tight phospholipid acyl chain packing in the mixed micelle.  相似文献   

14.
The 31P nuclear magnetic resonance (NMR) spectra of benzene solutions of hydrated dipalmitoyl lecithin (DPL) inverted micelles, with and without incorporated paramagnetic lanthanide ions, have been recorded. Individual resonances for micelles containing none, one, and two ions can be resolved and observed in the presence of one another. The relative intensities of these peaks yield some information on the state of aggregation of lipid inverted micelles prepared by ultrasonic irradiation. The relative intensities and chemical shifts of resonances of unsonicated mixtures of preformed micelles containing different numbers of ions per micelle indicate that some kind of equilibration occurs. The data are consistent with a selective fusion of multi-ion micelles with ion-free micelles. The NMR spectra place constraints on the lifetimes of metal ions and lipid and water molecules within a micelle before transfer to another.  相似文献   

15.
The N-terminal fusion domain of the HIV-1 gp41 envelope glycoprotein is responsible for initiating the fusion of viral and cellular membranes, leading to the subsequent infection of the host cell by HIV-1. We have investigated the backbone structure and dynamics of the 30 N-terminal residues of HIV-1 gp41 in membrane-mimicking environments using NMR spectroscopy and (15)N- and (15)N,(13)C,(2)H-labeled peptides. Similar (15)N-(1)H HSQC spectra were obtained in a variety of detergents, including SDS, DPC, mixed DPC/SDS, and LPPG micelles, indicating that the peptide structure is not strongly influenced by the type of detergent used. Detailed characterization was carried out in SDS micelles, where the long-term sample stability was found to be optimal. In addition to J-coupling and NOE restraints, a nearly complete set of backbone residual dipolar coupling restraints was recorded for the fusion domain-micelle complex aligned with respect to the magnetic field using a stretched polyacrylamide gel. Backbone amide (15)N spin relaxation and amide hydrogen exchange rates with the solvent were also measured. The ensemble of NMR structures reveals an uninterrupted alpha-helix for the least mobile residues (S(2) > 0.65), Ile-4 to Met-19, with transient helical character extending up to Ala-22. A 12-residue (Ile-4 to Ala-15) segment is fully shielded from solvent, with Gly-3 and Gly-16 found at micelle-solvent interfaces. Residues external to the micelle exhibit enhanced picosecond to nanosecond time scale dynamics relative to the residues buried in the micelle, and their mobility increases with the distance from the micelle.  相似文献   

16.
The role played by noncovalent interactions in inducing a stable secondary structure onto the sodium dodecyl sulfate (SDS) and dodecylphosphocholine (DPC) micelle-bound conformations of (Ala(8,13,18))magainin 2 amide and the DPC micelle bound conformation of magainin 1 were determined. Two-dimensional NMR and molecular modeling investigations indicated that (Ala(8,13,18))magainin 2 amide bound to DPC micelles adopts a alpha-helical secondary structure involving residues 2-16. The four C-terminal residues converge to a lose beta-turn structure. (Ala(8,13,18))magainin 2 amide bound to SDS miscelles adopts a alpha-helical secondary structure involving residues 7-18. The C- and N-terminal residues exhibited a great deal of conformational flexibility. Magainin 1 bound to DPC micelles adopts a alpha-helical secondary structure involving residues 4-19. The C-terminal residues converge to a lose beta-turn structure. The results of this investigation indicate hydrophobic interactions are the major contributors to stabilizing the induced helical structure of the micelle-bound peptides. Electrostatic interactions between the polar head groups of the micelle and the cationic side chains of the peptides define the positions along the peptide backbone where the helical structures begin and end.  相似文献   

17.
Cuthbertson JM  Bond PJ  Sansom MS 《Biochemistry》2006,45(48):14298-14310
The glycophorin helix dimer is a paradigm for the exploration of helix-helix interactions in integral membrane proteins. Two NMR structures of the dimer are known, one in a detergent micelle and one in a lipid bilayer. Multiple (4 x 50 ns) molecular dynamics simulations starting from each of the two NMR structures, with each structure in either a dodecyl phosphocholine (DPC) micelle or a dimyristoyl phosphatidylcholine (DMPC) bilayer, have been used to explore the conformational dynamics of the helix dimer. Analysis of the helix-helix interaction, mediated by the GxxxG sequence motif, suggests convergence of the simulations to a common model. This is closer to the NMR structure determined in a bilayer than to micelle structure. The stable dimer interface in the final simulation model is characterized by (i) Gly/Gly packing and (ii) Thr/Thr interhelix H-bonds. These results demonstrate the ability of extended molecular dynamics simulations in a lipid bilayer environment to refine membrane protein structures or models derived from experimental data obtained in protein/detergent micelles.  相似文献   

18.
The conformational features of Pam-Lys(0)-Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)-Ser(6)-Pro(7)-Phe(8)-Arg(9)-OH (PKD) and Pam-Gly(-1)-Lys(0)-Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)-Ser(6)-Pro(7)-Phe(8)-Arg(9)-OH (PGKD), the Pam-Lys and Pam-Gly-Lys analogues of bradykinin, have been determined by high-resolution NMR in a zwitterionic lipoid environment. Radical-induced relaxation of the (1)H NMR signals was used to probe the topological orientation of the peptides with respect to the zwitterionic lipid interface. The radical-induced relaxation and molecular dynamics (MD) data indicated that the palmitic acid and N-terminal amino acid residues embed into the micelles, while the rest of the polypeptide chain is closely associated with the water-micelle interface. Throughout the entire nuclear Overhauser effect restrained MD simulation, a nonideal type I beta-turn was observed in the C-terminus of PKD between residues 6 and 9, and a gamma-turn was observed in the C-terminus of PGKD between residues 6 and 7. Therefore, the additional glycine has a dramatic effect on the structural preferences of the biologically important C-terminus, an effect brought about by the interaction with the lipid environment. These structural features are correlated to the biological activity at the bradykinin B2 receptor.  相似文献   

19.
The filamentous coliphage M13 possesses multiple copies of a 50-residue coat protein which is inserted into the inner membrane of Escherichia coli during infection. 13C nuclear magnetic resonance (NMR) spectroscopy has been used to probe the structure and dynamics of M13 coat protein solubilized in detergent micelles. A comparison of backbone dynamics within the hydrophobic core region and the hydrophilic terminal domains was obtained by biosynthetic incorporation of [3-13C]alanine. Alanine is distributed throughout the protein and accounts for 10 residues (i.e., 20% of the total). Similar 13C NMR spectra of the protein have been obtained in two anionic detergents, sodium deoxycholate and sodium dodecyl sulfate, although the structures and physical properties of these solubilizing agents are quite different. The N-terminal alanine residues, assigned by pH titration, and the penultimate residue, assigned by carboxypeptidase A digestion, give rise to analogous peaks in both detergent systems. The pKa of Ala-1 (approximately 8.8) and the relaxation parameters of individual carbon atoms (T1, T2, and the nuclear Overhauser enhancement) are also generally similar, suggesting a similarity in the overall protein structure. Relaxation data have been analyzed according to the model-free approach of Lipari and Szabo [Lipari, G., & Szabo, A. (1982) J. Am. Chem. Soc. 104, 4546-4559]. The overall correlation times were obtained by fitting the three experimental relaxation values for a given well-resolved single carbon atom to obtain a unique value for the generalized order parameter, S2, and the effective correlation time, tau e. The former parameter reflects the spatial restriction of motion, and the latter, the rate.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

20.
The conformation of the cyclic portion (7-23) of naturally occurring rat atrial natriuretic factor, ANF(1-28), has been examined in sodium dodecyl sulfate (SDS) micelles using high-resolution NMR techniques. Evidence is presented which shows that ANF(7-23) has several regions of definable structure in SDS micelles which were not observed in earlier studies in bulk solvents. The 1H NMR resonances of ANF(7-23) in SDS micelles were assigned using sequential assignment techniques, and the conformational properties were analyzed primarily from proton-proton distances obtained from the quantitative analysis of two-dimensional nuclear Overhauser effect spectra. Three-dimensional structures consistent with the NMR data were generated by using distance geometry and constrained minimization/dynamics. Several similar but not identical structures were found which adequately satisfied the NMR constraints. Although none of the structures adopted a standard secondary structure, the conformations of three different sections of the peptide, 8-13, 14-17, and 18-21, were nearly identical in all of the predicted structures when individually superimposed.  相似文献   

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