Effect of Stapling on the Thermodynamics of mdm2–p53 Binding

Maity, Atanu; Choudhury, Asha Rani; Chakrabarti, Ramananda

doi:10.1021/acs.jcim.1c00219

Cited by 13 publications

(11 citation statements)

References 90 publications

(133 reference statements)

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“…The binding free energy is calculated using MMGBSA protocol as it is found to be a considerably accurate yet computationally less expensive method for binding energy estimation. [ 35 , 51 , 52 ]…”

Section: Resultsmentioning

confidence: 99%

“…Similar stepwise procedures were followed in an earlier work to successfully reproduce the favorable binding of stapled p53 peptide with mdm2 compared to wild type p53. [ 35 ]…”

Section: Methodsmentioning

confidence: 99%

“…Similar stepwise procedures were followed in an earlier work to successfully reproduce the favorable binding of stapled p53 peptide with mdm2 compared to wild type p53. [35] 3 | RESULTS study. [50] The higher fluctuations in that region in the presence of peptides are reflections of the direct interaction of the loop residues with the peptides.…”

Section: Binding Energy Calculationmentioning

confidence: 99%

“…considerably accurate yet computationally less expensive method for binding energy estimation. [35,51,52]…”

Section: Binding Energy Calculationmentioning

confidence: 99%

“…The changes in entropy in the process of complex formation by combining two moieties depends on their entropy in the free and bound Stapled peptides are known to reduce this entropic penalty by inducing conformational restriction to the free peptide. [35] The fluctuations of the peptides in their free and the RBD-bound state have been compared by calculating two properties, root mean square fluctuation (RMSF) of peptide residues and the helical propensity of the peptides.…”

Section: Conformational Restriction By Stapling Agent Contributes To ...mentioning

confidence: 99%

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Computational design of stapled peptide inhibitor against SARS‐CoV‐2 receptor binding domain

et al. 2022

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Since its first detection in 2019, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) has been the cause of millions of deaths worldwide. Despite the development and administration of different vaccines, the situation is still worrisome as the virus is constantly mutating to produce newer variants some of which are highly infectious. This raises an urgent requirement to understand the infection mechanism and thereby design therapeutic‐based treatment for COVID‐19. The gateway of the virus to the host cell is mediated by the binding of the receptor binding domain (RBD) of the virus spike protein to the angiotensin‐converting enzyme 2 (ACE2) of the human cell. Therefore, the RBD of SARS‐CoV‐2 can be used as a target to design therapeutics. The α1 helix of ACE2, which forms direct contact with the RBD surface, has been used as a template in the current study to design stapled peptide therapeutics. Using computer simulation, the mechanism and thermodynamics of the binding of six stapled peptides with RBD have been estimated. Among these, the one with two lactam stapling agents has shown binding affinity, sufficient to overcome RBD‐ACE2 binding. Analyses of the mechanistic detail reveal that a reorganization of amino acids at the RBD‐ACE2 interface produces favorable enthalpy of binding whereas conformational restriction of the free peptide reduces the loss in entropy to result higher binding affinity. The understanding of the relation of the nature of the stapling agent with their binding affinity opens up the avenue to explore stapled peptides as therapeutic against SARS‐CoV‐2.

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Section: Resultsmentioning

confidence: 99%

“…Similar stepwise procedures were followed in an earlier work to successfully reproduce the favorable binding of stapled p53 peptide with mdm2 compared to wild type p53. [ 35 ]…”

Section: Methodsmentioning

confidence: 99%

Section: Binding Energy Calculationmentioning

confidence: 99%

“…considerably accurate yet computationally less expensive method for binding energy estimation. [35,51,52]…”

Section: Binding Energy Calculationmentioning

confidence: 99%

Section: Conformational Restriction By Stapling Agent Contributes To ...mentioning

confidence: 99%

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Computational design of stapled peptide inhibitor against SARS‐CoV‐2 receptor binding domain

et al. 2022

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The Role of Structural Flexibility in Hydrocarbon‐Stapled Peptides Designed to Block Viral Infection via Human ACE2 Mimicry

Jiang,

Tian,

Nicolaescu

et al. 2024

Peptide Science

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The COVID‐19 pandemic drove a uniquely fervent pursuit to explore the potential of peptide, antibody, protein, and small‐molecule‐based antiviral agents against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). The interaction between the SARS‐CoV2 spike protein with the angiotensin‐converting enzyme 2 (ACE2) receptor that mediates viral cell entry was a particularly interesting target given its well‐described protein–protein interaction (PPI). This PPI is mediated by an α‐helical portion of ACE2 binding to the receptor binding domain (RBD) of the spike protein and thought to be susceptible to blockade through molecular mimicry. Small numbers of hydrocarbon‐stapled synthetic peptides designed to disrupt or block this interaction were tested individually and were found to have variable efficacy despite having related or overlapping sequences and similarly increased α‐helicity. Reasons for these differences are unclear and reported preclinical successes have been limited. This study sought to better understand reasons for these differences through evaluation of a comprehensive collection of hydrocarbon‐stapled peptides, designed based on four distinct principles: stapling position, number of staples, amino acid sequence, and primary sequence length. Surprisingly, we observed that the helicity and amino acid sequence iterations of hydrocarbon‐stapled peptides did not correlate with their bioactivity. Our results highlight the importance of iterative and combinatorial testing of these compounds to determine a configuration that best mimics natural binding and allows for chain flexibility while sacrificing structural helicity.

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Dissecting the geometric and hydrophobic constraints of stapled peptides

Li,

Tan,

Verma

2024

Proteins

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Stapled peptides are a promising class of molecules with potential as highly specific probes of protein–protein interactions and as therapeutics. Hydrocarbon stapling affects the peptide properties through the interplay of two factors: enhancing the overall hydrophobicity and constraining the conformational flexibility. By constructing a series of virtual peptides, we study the role of each factor in modulating the structural properties of a hydrocarbon‐stapled peptide PM2, which has been shown to enter cells, engage its target Mouse Double Minute 2 (MDM2), and activate p53. Hamiltonian replica exchange molecular dynamics (HREMD) simulations suggest that hydrocarbon stapling favors helical populations of PM2 through a combination of the geometric constraints and the enhanced hydrophobicity of the peptide. To further understand the conformational landscape of the stapled peptides along the binding pathway, we performed HREMD simulations by restraining the peptide at different distances from MDM2. When the peptide approaches MDM2, the binding pocket undergoes dehydration which appears to be greater in the presence of the stapled peptide compared with the linear peptide. In the binding pocket, the helicity of the stapled peptide is increased due to the favorable interactions between the peptide residues as well as the staple and the microenvironment of the binding pocket, contributing to enhanced affinity. The dissection of the multifaceted mechanism of hydrocarbon stapling into individual factors not only deepens fundamental understanding of peptide stapling, but also provides guidelines for the design of new stapled peptides.

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Effect of Stapling on the Thermodynamics of mdm2–p53 Binding

Cited by 13 publications

References 90 publications

Computational design of stapled peptide inhibitor against SARS‐CoV‐2 receptor binding domain

Computational design of stapled peptide inhibitor against SARS‐CoV‐2 receptor binding domain

The Role of Structural Flexibility in Hydrocarbon‐Stapled Peptides Designed to Block Viral Infection via Human ACE2 Mimicry

Dissecting the geometric and hydrophobic constraints of stapled peptides

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