Computational studies and peptidomimetic design for the human p53-MDM2 complex

Haizhen Andrew Zhong, Heather A. Carlson

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

The interaction between human p53 and MDM2 is a key event in controlling cell growth. Many studies have suggested that a p53 mimic would be sufficient to inhibit MDM2 to reduce cell growth in cancerous tissue. In order to design a potent p53 mimic, molecular dynamics (MD) simulations were used to examine the binding interface and the effect of mutating key residues in the human p53-MDM2 complex. The Generalized Born surface area (GBSA) method was used to estimate free energies of binding, and a computational alanine-scanning approach was used to calculate the relative effects in the free energy of binding for key mutations. Our calculations determine the free energy of binding for a model p53-MDM2 complex to be -7.4 kcal/mol, which is in very good agreement with the experimentally determined values (-6.6-8.8 kcal/mol). The alanine-scanning results are in good agreement with experimental data and calculations by other groups. We have used the information from our studies of human p53-MDM2 to design a β-peptide mimic of p53. MD simulations of the mimic bound to MDM2 estimate a free energy of binding of -8.8 kcal/mol. We have also applied alanine scanning to the mimic-MDM2 complex and reveal which mutations are most likely to alter the binding affinity, possibly giving rise to escape mutants. The mimic was compared to nutlins, a new class of inhibitors that block the formation of the p53-MDM2 complex. There are interesting similarities between the nutlins and our mimic, and the differences point to ways that both inhibitors may be improved. Finally, an additional hydrophobic pocket is noted in the interior of MDM2. It may be possible to design new inhibitors to take advantage of that pocket.

Original languageEnglish (US)
Pages (from-to)222-234
Number of pages13
JournalProteins: Structure, Function and Genetics
Volume58
Issue number1
DOIs
StatePublished - Jan 1 2005

Fingerprint

Peptidomimetics
Alanine
Free energy
Molecular Dynamics Simulation
Cell growth
Scanning
Molecular dynamics
Mutation
Growth
Computer simulation
Peptides
Tissue

Keywords

  • AMBER
  • Escape mutants
  • Free energy calculation
  • HDM2
  • Inhibitor
  • Molecular dynamics simulation
  • Protein mimic
  • β-peptide

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

Cite this

Computational studies and peptidomimetic design for the human p53-MDM2 complex. / Zhong, Haizhen Andrew; Carlson, Heather A.

In: Proteins: Structure, Function and Genetics, Vol. 58, No. 1, 01.01.2005, p. 222-234.

Research output: Contribution to journalArticle

@article{7bb293530ebc496d9d63781be966eeeb,
title = "Computational studies and peptidomimetic design for the human p53-MDM2 complex",
abstract = "The interaction between human p53 and MDM2 is a key event in controlling cell growth. Many studies have suggested that a p53 mimic would be sufficient to inhibit MDM2 to reduce cell growth in cancerous tissue. In order to design a potent p53 mimic, molecular dynamics (MD) simulations were used to examine the binding interface and the effect of mutating key residues in the human p53-MDM2 complex. The Generalized Born surface area (GBSA) method was used to estimate free energies of binding, and a computational alanine-scanning approach was used to calculate the relative effects in the free energy of binding for key mutations. Our calculations determine the free energy of binding for a model p53-MDM2 complex to be -7.4 kcal/mol, which is in very good agreement with the experimentally determined values (-6.6-8.8 kcal/mol). The alanine-scanning results are in good agreement with experimental data and calculations by other groups. We have used the information from our studies of human p53-MDM2 to design a β-peptide mimic of p53. MD simulations of the mimic bound to MDM2 estimate a free energy of binding of -8.8 kcal/mol. We have also applied alanine scanning to the mimic-MDM2 complex and reveal which mutations are most likely to alter the binding affinity, possibly giving rise to escape mutants. The mimic was compared to nutlins, a new class of inhibitors that block the formation of the p53-MDM2 complex. There are interesting similarities between the nutlins and our mimic, and the differences point to ways that both inhibitors may be improved. Finally, an additional hydrophobic pocket is noted in the interior of MDM2. It may be possible to design new inhibitors to take advantage of that pocket.",
keywords = "AMBER, Escape mutants, Free energy calculation, HDM2, Inhibitor, Molecular dynamics simulation, Protein mimic, β-peptide",
author = "Zhong, {Haizhen Andrew} and Carlson, {Heather A.}",
year = "2005",
month = "1",
day = "1",
doi = "10.1002/prot.20275",
language = "English (US)",
volume = "58",
pages = "222--234",
journal = "Proteins: Structure, Function and Bioinformatics",
issn = "0887-3585",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - Computational studies and peptidomimetic design for the human p53-MDM2 complex

AU - Zhong, Haizhen Andrew

AU - Carlson, Heather A.

PY - 2005/1/1

Y1 - 2005/1/1

N2 - The interaction between human p53 and MDM2 is a key event in controlling cell growth. Many studies have suggested that a p53 mimic would be sufficient to inhibit MDM2 to reduce cell growth in cancerous tissue. In order to design a potent p53 mimic, molecular dynamics (MD) simulations were used to examine the binding interface and the effect of mutating key residues in the human p53-MDM2 complex. The Generalized Born surface area (GBSA) method was used to estimate free energies of binding, and a computational alanine-scanning approach was used to calculate the relative effects in the free energy of binding for key mutations. Our calculations determine the free energy of binding for a model p53-MDM2 complex to be -7.4 kcal/mol, which is in very good agreement with the experimentally determined values (-6.6-8.8 kcal/mol). The alanine-scanning results are in good agreement with experimental data and calculations by other groups. We have used the information from our studies of human p53-MDM2 to design a β-peptide mimic of p53. MD simulations of the mimic bound to MDM2 estimate a free energy of binding of -8.8 kcal/mol. We have also applied alanine scanning to the mimic-MDM2 complex and reveal which mutations are most likely to alter the binding affinity, possibly giving rise to escape mutants. The mimic was compared to nutlins, a new class of inhibitors that block the formation of the p53-MDM2 complex. There are interesting similarities between the nutlins and our mimic, and the differences point to ways that both inhibitors may be improved. Finally, an additional hydrophobic pocket is noted in the interior of MDM2. It may be possible to design new inhibitors to take advantage of that pocket.

AB - The interaction between human p53 and MDM2 is a key event in controlling cell growth. Many studies have suggested that a p53 mimic would be sufficient to inhibit MDM2 to reduce cell growth in cancerous tissue. In order to design a potent p53 mimic, molecular dynamics (MD) simulations were used to examine the binding interface and the effect of mutating key residues in the human p53-MDM2 complex. The Generalized Born surface area (GBSA) method was used to estimate free energies of binding, and a computational alanine-scanning approach was used to calculate the relative effects in the free energy of binding for key mutations. Our calculations determine the free energy of binding for a model p53-MDM2 complex to be -7.4 kcal/mol, which is in very good agreement with the experimentally determined values (-6.6-8.8 kcal/mol). The alanine-scanning results are in good agreement with experimental data and calculations by other groups. We have used the information from our studies of human p53-MDM2 to design a β-peptide mimic of p53. MD simulations of the mimic bound to MDM2 estimate a free energy of binding of -8.8 kcal/mol. We have also applied alanine scanning to the mimic-MDM2 complex and reveal which mutations are most likely to alter the binding affinity, possibly giving rise to escape mutants. The mimic was compared to nutlins, a new class of inhibitors that block the formation of the p53-MDM2 complex. There are interesting similarities between the nutlins and our mimic, and the differences point to ways that both inhibitors may be improved. Finally, an additional hydrophobic pocket is noted in the interior of MDM2. It may be possible to design new inhibitors to take advantage of that pocket.

KW - AMBER

KW - Escape mutants

KW - Free energy calculation

KW - HDM2

KW - Inhibitor

KW - Molecular dynamics simulation

KW - Protein mimic

KW - β-peptide

UR - http://www.scopus.com/inward/record.url?scp=10844238962&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10844238962&partnerID=8YFLogxK

U2 - 10.1002/prot.20275

DO - 10.1002/prot.20275

M3 - Article

VL - 58

SP - 222

EP - 234

JO - Proteins: Structure, Function and Bioinformatics

JF - Proteins: Structure, Function and Bioinformatics

SN - 0887-3585

IS - 1

ER -