The Last Secret of Protein Folding: The Real Relationship Between Long-Range Interactions and Local Structures

Cao, Aoneng

doi:10.1007/s10930-020-09925-w

Cited by 10 publications

(19 citation statements)

References 82 publications

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“…The CD spectra of the free peptides (Figure S7) show typical CD spectral features of the unstructured conformation. To restore the native α‐helix of TAD peptide, the AuNP‐peptide conjugates were first incubated at different temperatures, letting the favorable enthalpy of the native conformation of TAD peptide drive the move of the adatoms with Au−S bonds to the suitable positions on the surface of AuNPs [10,11] . Generally speaking, high temperature will accelerate the movement of adatoms, but over a certain value, high temperature might denature the native conformation of the peptides, making the conformational engineering impossible.…”

Section: Resultsmentioning

confidence: 99%

“…Besides the previous CDR loops, [3,7] we have shown here that the native conformation of the α‐helical fragment of natural proteins can also be restored on AuNPs. Actually, according to the confined lowest energy fragment (CLEF) hypothesis, [10,11] all kinds of structural fragments of natural proteins could be correctly reconstructed on NPs. The fundamental mechanism of the conformational engineering could be simply illustrated by the energy landscapes shown in Figure 7.…”

Section: Resultsmentioning

confidence: 99%

“…The dramatic different performance between human‐made nanomaterials and proteins is due to the fact that proteins fold precisely into unique conformations with “irregular” yet well‐defined surfaces. So the most challenging part for protein‐mimicking is to precisely organize non‐functional surface groups on NPs into specific 3D conformations to function in a concerted and orchestrated manner, just like the protein folding [10,11] …”

Section: Introductionmentioning

confidence: 99%

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A Potential MDM2 Inhibitor Formed by Restoring the Native Conformation of the p53 α‐Helical Peptide on Gold Nanoparticles

et al. 2022

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Many efforts have been made to develop inhibitors of MDM2 as potential drugs for cancer therapy. In this work, we use our previous developed conformational engineering technique to stabilize the binding conformation of the p53 transcription activation domain (TAD) peptide on gold nanoparticles (AuNPs), and create an AuNP‐based anti‐MDM2 artificial antibody, denoted as anti‐MDM2 Goldbody, that specifically binds MDM2. Though the free TAD peptide is unstructured, circular dichroism (CD) spectra confirm that its α‐helical conformation in the original p53 protein is restored on the anti‐MDM2 Goldbody, and surface plasmon resonance (SPR) experiments confirm that there is strong specific interaction between the anti‐MDM2 Goldbody and MDM2, demonstrating the anti‐MDM2 Goldbody as a potential inhibitor of MDM2. This work demonstrates that the conformational engineering technique is not limited to the antigen‐antibody systems, but can also be applied more widely in other protein‐protein interfaces to create increasingly more artificial proteins for various biomedical applications.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Potential MDM2 Inhibitor Formed by Restoring the Native Conformation of the p53 α‐Helical Peptide on Gold Nanoparticles

et al. 2022

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“…To answer this fundamental question, we proposed the “Confined Lowest Energy Structure Fragment” (CLESF) hypothesis ( Cao, 2020a ) (later unified as the CLEF hypothesis ( Cao, 2020b )) for the protein folding problem. The main idea of the CLEF hypothesis is that the whole peptide chain of a protein can be divided into many CLEFs.…”

Section: Discussionmentioning

confidence: 99%

“…The natural protein folding can be regarded as a special case of molecular conformational engineering. However, even the special case of protein folding is still not fully understood ( Cao, 2020a , 2020b ; Dill and MacCallum, 2012 ; Narayan et al., 2000 ); the general task of molecular conformational engineering is apparently a grand challenge.…”

Section: Introductionmentioning

confidence: 99%

Conformationally engineering flexible peptides on silver nanoparticles

et al. 2022

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Anti‐Carbonic Anhydrase Goldbodies by Conformational Reconstruction of the Complementary‐Determining Regions of Phage‐Displayed Antibodies

et al. 2023

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It has been demonstrated that the main complementary‐determining region (CDR) fragments of antibodies could be grafted onto gold nanoparticles (AuNPs) to produce artificial antibody, dubbed Goldbody. Goldbody maintains the same binding specificity with the corresponding antigen as the original antibody, but has better stability than the antibody. However, the current design of Goldbodies is mainly based on the structures of antibody‐antigen complexes. To extend this promising technique to the majority of antibodies whose complexes with the corresponding antigens are not structurally solved, herein, two anti‐carbonic anhydrase (CA) antibodies screened by phage display were chosen to create anti‐CA Goldbodies. One of the anti‐CA antibodies, cAb‐CA05, has a known complex structure with CA; but the other, cAb‐CA06, does not. By conformational reconstruction of the CDR3 of cAb‐CA06, which is identified by sequence alignment, as well as the CDR3 of cAb‐CA05, two anti‐CA Goldbodies have been created. Interestingly, our results show the two Goldbodies can bind to CA simultaneously, unambiguously indicating their binding sites on CA are far away. As the CDR3 is the major binding unit for many antibodies, which can be reliably predicted by sequence alignment, it could be used as a general strategy to develop artificial antibodies by directly grafting and conformationally reconstructing the predicted CDR3 of antibodies.

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The Last Secret of Protein Folding: The Real Relationship Between Long-Range Interactions and Local Structures

Cited by 10 publications

References 82 publications

A Potential MDM2 Inhibitor Formed by Restoring the Native Conformation of the p53 α‐Helical Peptide on Gold Nanoparticles

A Potential MDM2 Inhibitor Formed by Restoring the Native Conformation of the p53 α‐Helical Peptide on Gold Nanoparticles

Conformationally engineering flexible peptides on silver nanoparticles

Anti‐Carbonic Anhydrase Goldbodies by Conformational Reconstruction of the Complementary‐Determining Regions of Phage‐Displayed Antibodies

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