Accounting for a mirror-image conformation as a subtle effect in protein folding

Kachlishvili, Khatuna; Maisuradze, Gia G.; Martin, Osvaldo A.; Liwo, Adam; Vila, Jorge A.; Scheraga, Harold A.

doi:10.1073/pnas.1407837111

Cited by 20 publications

(31 citation statements)

References 37 publications

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“…It is essential for them to selectively fold into functional and unique 3D structures because their misfoldings can lead to the malfunctioning of the proteins and cause various disorders such as Alzheimer's, and Parkinson's diseases. 1,2 Understanding the protein folding within biological membrane is therefore the key to unlocking their ability to manipulate biological systems and potential role in treating diseases. [3][4][5] Despite the importance of membrane protein folding, a molecular level understanding of the folding mechanisms is generally much less comprehensive than that for the water-soluble proteins.…”

Section: Introductionmentioning

confidence: 99%

Amide III SFG Signals as a Sensitive Probe of Protein Folding at Cell Membrane Surface

Huang

Tian

et al. 2016

J. Phys. Chem. C

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A good understanding of membrane protein folding at the molecular level requires an effective means to determine the dynamical structural changes on coil-to-helix transition within cell membrane, yet remains challenging. Herein, we demonstrate that the amide III spectral signals of protein backbone, generated in the sum frequency generation vibrational spectroscopy, are a powerful tool to probe the protein folding processes within the membrane in situ, in real time and without exogenous labels. The amide III signals are capable of separating the spectral profiles of the random-coil and α-helical structures at the interface. The intensity ratio of coil and helix peaks becomes a prime indicator that allows to directly capturing the dynamical change of the coil-helix transition. With this approach, using pardaxin as model, the influence of lipid charge on the peptide folding degree at cell membrane surface has been nicely elucidated. It is evident that negative charge of lipid increases the folding degree of pardaxin upon interfacial adsorption and promotes the formation of α-helical structure during the insertion of peptide into lipid bilayer. This robust spectral approach can thus greatly enhance our ability to monitor the dynamics of membrane proteins in a real cell environment in situ.

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Section: Introductionmentioning

confidence: 99%

Amide III SFG Signals as a Sensitive Probe of Protein Folding at Cell Membrane Surface

Huang

Tian

et al. 2016

J. Phys. Chem. C

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“…12). The fourth one led to a mirror-image conformation, the reason for which has now been proposed (Kachlishvili et al 2014). It was shown that the formation of the mirror-image conformation (see Fig.…”

Section: Protein Folding With Eceppmentioning

confidence: 91%

My 65 years in protein chemistry

Scheraga

2015

Quart. Rev. Biophys.

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This is a tour of a physical chemist through 65 years of protein chemistry from the time when emphasis was placed on the determination of the size and shape of the protein molecule as a colloidal particle, with an early breakthrough by James Sumner, followed by Linus Pauling and Fred Sanger, that a protein was a real molecule, albeit a macromolecule. It deals with the recognition of the nature and importance of hydrogen bonds and hydrophobic interactions in determining the structure, properties, and biological function of proteins until the present acquisition of an understanding of the structure, thermodynamics, and folding pathways from a linear array of amino acids to a biological entity. Along the way, with a combination of experiment and theoretical interpretation, a mechanism was elucidated for the thrombin-induced conversion of fibrinogen to a fibrin blood clot and for the oxidative-folding pathways of ribonuclease A. Before the atomic structure of a protein molecule was determined by x-ray diffraction or nuclear magnetic resonance spectroscopy, experimental studies of the fundamental interactions underlying protein structure led to several distance constraints which motivated the theoretical approach to determine protein structure, and culminated in the Empirical Conformational Energy Program for Peptides (ECEPP), an all-atom force field, with which the structures of fibrous collagen-like proteins and the 46-residue globular staphylococcal protein A were determined. To undertake the study of larger globular proteins, a physics-based coarse-grained UNited-RESidue (UNRES) force field was developed, and applied to the protein-folding problem in terms of structure, thermodynamics, dynamics, and folding pathways. Initially, single-chain and, ultimately, multiple-chain proteins were examined, and the methodology was extended to protein–protein interactions and to nucleic acids and to protein–nucleic acid interactions. The ultimate results led to an understanding of a variety of biological processes underlying natural and disease phenomena.

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“…This protein has been the subject of extensive theoretical (Olszewski, Kolinski & Skolnick, 1996;Vila, Ripoll & Scheraga, 2003;Garcia & Onuchic, 2003;Lee et al, 2006;Kachlishvili et al, 2014) and experimental (Deisenhofer, 1981;Gouda et al, 1992;Bai et al, 1997;Myers & Oas, 2001;Sato et al, 2004;Dimitriadis et al, 2004;Noel et al, 2012) studies because of its biological importance and small size. In contrast to this, the mirror-image conformation has been subject of limited discussion (Olszewski, Kolinski & Skolnick, 1996;Vila, Ripoll & Scheraga, 2003;Garcia & Onuchic, 2003;Noel et al, 2012;Kachlishvili et al, 2014). The reason for this might be that the mirror image conformation of this protein has been observed only in some theoretical studies with different force fields but it has never been detected experimentally.…”

Section: Introductionmentioning

confidence: 99%

Outline of an experimental design aimed to detect protein A mirror image in solution

Martin

Vorobjev

Scheraga

et al. 2019

PeerJ Physical Chemistry

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There is abundant theoretical evidence indicating that a mirror image of Protein A may occur during the protein folding process. However, as to whether such mirror image exists in solution is an unsolved issue. Here we provide outline of an experimental design aimed to detect the mirror image of Protein A in solution. The proposal is based on computational simulations indicating that the use of a mutant of protein A, namely Q10H, could be used to detect the mirror image conformation in solution. Our results indicate that the native conformation of the protein A should have a pKa, for the Q10H mutant, at ≈6.2, while the mirror-image conformation should have a pKa close to ≈7.3. Naturally, if all the population is in the native state for the Q10H mutant, the pKa should be ≈6.2, while, if all are in the mirror-image state, it would be ≈7.3, and, if it is a mixture, the pKa should be larger than 6.2, presumably in proportion to the mirror population. In addition, evidence is provided indicating the tautomeric distribution of H10 must also change between the native and mirror conformations. Although this may not be completely relevant for the purpose of determining whether the protein A mirror image exists in solution, it could provide valuable information to validate the pKa findings. We hope this proposal will foster experimental work on this problem either by direct application of our proposed experimental design or serving as inspiration and motivation for other experiments.

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Accounting for a mirror-image conformation as a subtle effect in protein folding

Cited by 20 publications

References 37 publications

Amide III SFG Signals as a Sensitive Probe of Protein Folding at Cell Membrane Surface

Amide III SFG Signals as a Sensitive Probe of Protein Folding at Cell Membrane Surface

My 65 years in protein chemistry

Outline of an experimental design aimed to detect protein A mirror image in solution

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