Conformational interconversion in compstatin probed with molecular dynamics simulations

Mallik, Buddhadeb; Lambris, John D.; Morikis, Dimitrios

doi:10.1002/prot.10491

Cited by 24 publications

(53 citation statements)

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“…Studies have been reported in which unfavorable entropy changes were ascribed to configurational changes in the ligand upon binding (42) or to protein conformational changes upon binding (43). Molecular dynamic simulations carried out on the ensemble of energy-minimized NMR structures suggested that V4H9 exists as multiple conformers in solution (44). The authors reported five major conformers of compstatin in solution: The most populated is the coil conformation with a type I ␤-turn occupying about 44% of the conformational space, which resembles the average energy minimized conformation obtained from NMR studies.…”

Section: Discussionmentioning

confidence: 99%

“…Based on these observations and the negative heat capacity changes observed in the present study, we propose that compstatin exists as a coil before binding and shows a propensity to undergo configurational changes to a more structured ␤-hairpin after binding. This interconversion has a low free energy barrier, showing a higher probability for the peptide to assume a ␤-hairpin conformation from the coil conformation (44).…”

Section: Discussionmentioning

confidence: 99%

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Thermodynamic Studies on the Interaction of the Third Complement Component and Its Inhibitor, Compstatin

Katragadda

Morikis

Lambris

2004

Journal of Biological Chemistry

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Compstatin is a 13-residue cyclic peptide that inhibits complement activation by binding to complement component, C3. Although the activity of compstatin has been improved severalfold using combinatorial and rational design approaches, the molecular basis for its interaction with C3 is not yet fully understood. In the present study, isothermal titration calorimetry was employed to dissect the molecular forces that govern the interaction of compstatin with C3 using four different compstatin analogs. Our studies indicate that the C3-compstatin interaction is an enthalpy-driven process. Substitution of the valine and histidine residues at positions 4 and 9 with tryptophan and alanine, respectively, resulted in the increase of enthalpy of the interaction, thereby increasing the binding affinity for C3. The data also suggest that the interaction is mediated by water molecules. These interfacial water molecules could be the source for unfavorable entropy and large negative heat capacity changes observed in the interaction. Although part of the negative heat capacity changes could be accounted for by the water molecules, the rest might be resulting from the conformational changes in C3 and/or compstatin up on binding. Finally, we propose based on the pK a values determined from the protonation studies that histidine on compstatin participates in protonation changes and contributes to the specificity of the interaction between compstatin and C3. These protonation changes vary significantly between the binding of different compstatin analogs to C3.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Thermodynamic Studies on the Interaction of the Third Complement Component and Its Inhibitor, Compstatin

Katragadda

Morikis

Lambris

2004

Journal of Biological Chemistry

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“…The original 21 PDB structures are all in coil conformations. However, after minimization, a hhairpin (bcompstatinN 2 ) as well as 3 10 -helix structures (bcompstatinN 18 and bcompstatinN 20 ) [17] appeared (see the third column in Table 2). 3 10 -Helices are formed in the turn position with a relatively high energy.…”

Section: Resultsmentioning

confidence: 99%

“…However, for real proteins, all-atom representations that include all pairwise interactions and solvation effects fail to characterize the energy landscape, since they require astronomical amounts of CPU time. Mallik et al [17] has investigated the energy landscape of compstatin using 1-ns molecular dynamics (MD) simulations starting from the 21 NMR structures [14], using a CHARMM force field with a continuum solvent model. They found three kinds of conformers, coil with a h-turn, h-hairpin with a h-turn, and an a-helix, at the end of their MD simulation.…”

Section: Introductionmentioning

confidence: 99%

Understanding the structural characteristics of compstatin by conformational space annealing

Song

Kim

Lee

2005

Biophysical Chemistry

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The structural characteristics of the 13-residue compstatin molecule are investigated using the conformational space annealing (CSA) method with CHARMM force field and the GBSA continuum solvent model. In order to sample conformations in the energy range of the minimized NMR structures, we have used the stopping criterion to the CSA search when a conformation whose energy is less than À490 kcal/mol is found. With this stopping criterion, a great variety of conformations are generated around experimentally known structures. Twenty independent CSA runs starting from random states find 1000 representative conformations in the energy landscape of the compstatin, which are classified into thirty-one structural families. The majority of the conformations (94.4%) are in the coil state. Other conformers containing a 3 10 -helix, a k-helix, a h-hairpin, and an a-helix are also found. D

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“…4). The arsenal of active and inactive analogs in combination with the known solution structures led to the development of sophisticated in silico models based on QSAR, molecular dynamics, or conformational space annealing (Mallik et al 2003;Mulakala et al 2007;Song et al 2005;Tamamis et al 2007). However, the most important breakthrough was reached with the release of the first co-crystal structure between a compstatin analog and C3c (see Chap.…”

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confidence: 99%

Compstatin: A Complement Inhibitor on its Way to Clinical Application

Ricklin

Lambris²

2008

Advances in Experimental Medicine and Biology

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118

166

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Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic. Tackling Complement at its CoreTherapeutic intervention in the human complement system has long been recognized as a promising strategy for the treatment of a series of ischemic, inflammatory and autoimmune diseases (Lambris and Holers 2000;Ricklin and Lambris 2007a). In principle, the large network of soluble and cell-surface-bound proteins, which builds the base of the complement cascade, offers a variety of potential drug targets. However, the quest for complement-specific therapeutics proved to be much more challenging than initially anticipated. With the therapeutic antibody eculizumab (Soliris ® , Alexion Pharmaceuticals, Inc.) against paroxysmal nocturnal hemoglobinuria, the first drug with proven complement connectivity has been marketed only recently (Ricklin and Lambris 2007a;Rother et al. 2007). A second complement-associated compound, purified C1 esterase inhibitor (C1-INH), is available as a therapeutic option for the treatment of hereditary angioedema in several countries. However, its mechanism of action may be closer related to the bradykinin-kallikrein than the complement cascade (Davis 2006). Strikingly, both drugs cover relatively rare diseases and have been developed with the aid of orphan drug regulations. Yet, for many of the more common inflammatory or autoimmune conditions there are no complement drugs on the market. Any extension of the current complement-specific therapeutic arsenal is therefore highly desired.Part of the problem in complement-directed drug discovery is the selection of the right target (Ricklin and Lambris 2007a activation is considered to be the most promising approach in many cases. On a molecular level, inhibition at the level of C3, including the C3 convertases, is of particular interest since both the amplification of all initiation pathways and the generatio...

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Conformational interconversion in compstatin probed with molecular dynamics simulations

Cited by 24 publications

References 46 publications

Thermodynamic Studies on the Interaction of the Third Complement Component and Its Inhibitor, Compstatin

Thermodynamic Studies on the Interaction of the Third Complement Component and Its Inhibitor, Compstatin

Understanding the structural characteristics of compstatin by conformational space annealing

Compstatin: A Complement Inhibitor on its Way to Clinical Application

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