Characterization of flexible molecules in solution: the RGDW peptide 1 1Edited by B. Honig

Bartels, Christian; Stote, Roland H.; Karplus, Martin

doi:10.1006/jmbi.1998.2255

Cited by 26 publications

(30 citation statements)

References 62 publications

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“…in the binding of RGDW with platelet glycoprotein IIb-IIIa (26). The lower capability of RGD peptides to assume the folded conformations, compared with NGR sequences, is likely related to the presence of two charged groups instead of one, which force the peptide to assume an extended conformation to obtain optimal solvation of charged side chains, as shown by Karplus and co-workers (24). In contrast, in NGR peptides the free energy gain obtained with solvation of only one charged side chain is more favorable in the folded conformations (the solvent accessible surface of Arg 4 is 2.0 nm 2 for state B and 1.4 nm 2 for state A), where the formation of intramolecular interactions may further contribute to stabilize the folded state.…”

Section: Figmentioning

confidence: 96%

“…Also in this case, structure-activity relationship studies showed that a folded structure is necessary for activity. Although theoretical and NMR-based experimental studies showed the presence of turn geometry also in the RGD sequence, centered on the glycine residue, the extreme conformational freedom of RGD makes, in this case, the open structure more favorable (24,25). For this reason, the presence of conformational constraints is necessary to obtain the optimal geometry for receptor recognition, e.g.…”

Section: Figmentioning

confidence: 99%

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Structure-Activity Relationships of Linear and Cyclic Peptides Containing the NGR Tumor-homing Motif

Colombo

Curnis

Mori

et al. 2002

Journal of Biological Chemistry

173

136

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Cyclic and linear peptides containing the Asn-Gly-Arg (NGR) motif have proven useful for delivering various anti-tumor compounds and viral particles to tumor vessels. We have investigated the role of cyclic constraints on the structure and tumor-homing properties of NGR peptides using tumor necrosis factor-␣ (TNF) derivatives containing disulfide-bridged (CNGRC-TNF) and linear (GNGRG-TNF) NGR domains. Experiments carried out in animal models showed that both GNGRG and CNGRC can target TNF to tumors. However, the antitumor activity of CNGRC-TNF was >10-fold higher than that of GNGRG-TNF. Molecular dynamic simulation of cyclic CNGRC showed the presence of a bend geometry involving residues Gly 3 -Arg 4 . Molecular dynamic simulation of the same peptide without disulfide constraints showed that the most populated and thermodynamically favored configuration is characterized by the presence of a ␤-turn involving residues Gly 3 -Arg 4 and hydrogen bonding interactions between the backbone atoms of Asn 2 and Cys 5 . These results suggest that the NGR motif has a strong propensity to form ␤-turn in linear peptides and may explain the finding that GNGRG peptide can target TNF to tumors, albeit to a lower extent than CNGRC. The disulfide bridge constraint is critical for stabilizing the bent conformation and for increasing the tumor targeting efficiency.Phage display peptide libraries are commonly used to obtain peptide sequences interacting with proteins differentially expressed in normal and pathological tissues (1, 2). For instance, in vivo panning of phage libraries in tumor-bearing animals have proven useful for selecting peptides able to interact with proteins expressed within tumor-associated vessels and to home to neoplastic tissues (3). Among the various tumor targeting ligands identified so far, the CNGRC peptide have proven useful for delivering various anti-tumor compounds, like chemotherapeutic drugs, apoptotic peptides and cytokines, to tumor vessels (3-5). For example, we have recently shown that targeted delivery of tumor necrosis factor-␣ (TNF) 1 to tumor vasculature can be obtained by coupling its N terminus to the C terminus of the CNGRC peptide, by genetic engineering technology (5). This approach markedly improved the therapeutic index of TNF in animal models, either when used alone (5) or in combination with chemotherapeutic agents (6). Studies on the mechanism of action showed that the targeting domain of this TNF derivative (called NGR-TNF) binds an aminopeptidase (CD13) isoform expressed in tumor vessels, and not other isoforms expressed in normal epithelia or myeloid cells (7). Besides CNGRC, other tumor vasculature targeting peptides containing the NGR motif have been identified, such as linear NGRAHA and cyclic CVLNGRMEC (3). These and other linear and cyclic NGR peptides have been used for targeting viral particles to endothelial cells (8, 9). Although these findings may suggest that peptide cyclization is not necessary for the targeting properties of NGR peptides, the role of cysteines and th...

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Section: Figmentioning

confidence: 96%

Section: Figmentioning

confidence: 99%

Structure-Activity Relationships of Linear and Cyclic Peptides Containing the NGR Tumor-homing Motif

Colombo

Curnis

Mori

et al. 2002

Journal of Biological Chemistry

173

136

View full text Add to dashboard Cite

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“…Of the four RGDW simulations, one shows no population in the``active'' region around 0.0°and a large distribution between 60°a nd 180°; the other three RGDW simulations sample conformations in the``active'' region. In the umbrella sampling simulations of Bartels et al [43] (Fig. 4C), the RGDW peptide tends to populate regions outside the active region, although a small population in the active region is found.…”

Section: Resultsmentioning

confidence: 91%

“…For these proteins, the Ca-Ca distances ranged from 5.3 to 7.3 A Ê , the Cb-Cb distances ranged from 6.0 to 9.6 A Ê and the Cf-Cc distances ranged from 9. [36], c from the adaptive umbrella sampling simulations of RGDW from Bartels et al [43] and d from D RGDW simulations of Stote et al [36] space available to the sidechains, while the pseudodihedral angle /[Cf(R)-Ca(R)-Ca(D)-Cc(D)] may be important for optimizing the interactions. As mentioned previously, the narrower distribution of dihedral angles for D RGDW in the active region of the conformational space may reduce the entropy cost for assuming an active conformation.…”

Section: Resultsmentioning

confidence: 99%

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Analysis of the RGD sequence in protein structures: comparison to the conformations of the RGDW and D RGDW peptides determined by molecular dynamics simulations

Stote¹

2001

Theoretical Chemistry Accounts: Theory, Computation, and Modeli

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Geometric properties of the RGD sequence in a data set of protein crystal and NMR structures deposited in the Protein Data Bank were examined to identify structural characteristics that are related to cell adhesion activity. Interatomic distances and dihedral angles are examined. These geometric measures are then used in an analysis of the conformations of the RGDW and D RGDW peptides obtained from molecular dynamics simulations (Stote RH, et al. (2000) J Phys Chem B 104:1624). This analysis leads to the suggestion that dierences in the accessible conformations contribute to the dierence in biological activity between the RGDW and the D RGDW peptides.

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Enhanced conformational diversity search of CDR-H3 in antibodies: Role of the first CDR-H3 residue

Kim

Shirai²,

Nakajima³

et al. 1999

Proteins

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Through a conformation search by a simulation calculation, the relationships between the amino acid sequences and the conformations of the third complementarity-determining region of the antibody heavy chain (CDR-H3) were investigated to characterize the large conformational varieties of antibodies. Here, we focused on the structural role of the first CDR-H3 residue, and we selected two antibodies, 28B4 and PLG, whose CDR-H3 conformations are significantly different, having Trp and Gly at the first position, respectively. Multicanonical molecular dynamics simulations, with the advantage of enhanced sampling efficiency, were performed for the CDR-H3 fragments of 28B4 and PLG, and a modified CDR-H3 model of 28B4, where the first Trp residue was substituted with Gly. When the first CDR-H3 residue is Trp, almost all of the observed CDR-H3 loops were bent at the first residue. In contrast, when the first residue is Gly, large varieties of loop conformations were observed. The structural role of this Gly residue is discussed from the perspective of the other antibody structures in the database. When the surrounding residues were included in the calculations, CDR-H3 loop structures similar to those in the crystal structures were reproduced as the major conformations for both the 28B4 and PLG antibodies.

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Characterization of flexible molecules in solution: the RGDW peptide 1 1Edited by B. Honig

Cited by 26 publications

References 62 publications

Structure-Activity Relationships of Linear and Cyclic Peptides Containing the NGR Tumor-homing Motif

Structure-Activity Relationships of Linear and Cyclic Peptides Containing the NGR Tumor-homing Motif

Analysis of the RGD sequence in protein structures: comparison to the conformations of the RGDW and D RGDW peptides determined by molecular dynamics simulations

Enhanced conformational diversity search of CDR-H3 in antibodies: Role of the first CDR-H3 residue

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