Molecular dynamics simulation of β 2-microglobulin in denaturing and stabilizing conditions

Federico Fogolari, Alessandra Corazza, Nicola Varini, Matteo Rotter, Devrim Gumral, Luca Codutti, Enrico Rennella, Paolo Viglino, Vittorio Bellotti, Gennaro Esposito

Research output: Contribution to journalArticle

Abstract

β 2-Microglobulin has been a model system for the study of fibril formation for 20 years. The experimental study of β 2-microglobulin structure, dynamics, and thermodynamics in solution, at atomic detail, along the pathway leading to fibril formation is difficult because the onset of disorder and aggregation prevents signal resolution in Nuclear Magnetic Resonance experiments. Moreover, it is difficult to characterize conformers in exchange equilibrium. To gain insight (at atomic level) on processes for which experimental information is available at molecular or supramolecular level, molecular dynamics simulations have been widely used in the last decade. Here, we use molecular dynamics to address three key aspects of β 2-microglobulin, which are known to be relevant to amyloid formation: (1) 60 ns molecular dynamics simulations of β 2-microglobulin in trifluoroethanol and in conditions mimicking low pH are used to study the behavior of the protein in environmental conditions that are able to trigger amyloid formation; (2) adaptive biasing force molecular dynamics simulation is used to force cis-trans isomerization at Proline 32 and to calculate the relative free energy in the folded and unfolded state. The native-like trans-conformer (known as intermediate 2 and determining the slow phase of refolding), is simulated for 10 ns, detailing the possible link between cis-trans isomerization and conformational disorder; (3) molecular dynamics simulation of highly concentrated doxycycline (a molecule able to suppress fibril formation) in the presence of β 2-microglobulin provides details of the binding modes of the drug and a rationale for its effect.

Original languageEnglish (US)
Pages (from-to)986-1001
Number of pages16
JournalProteins: Structure, Function and Bioinformatics
Volume79
Issue number3
DOIs
StatePublished - Mar 1 2011

Fingerprint

Molecular Dynamics Simulation
Molecular dynamics
Computer simulation
Isomerization
Amyloid
Trifluoroethanol
Doxycycline
Thermodynamics
Proline
Free energy
Magnetic Resonance Spectroscopy
Agglomeration
Nuclear magnetic resonance
Molecules
Pharmaceutical Preparations
Proteins
Experiments

Keywords

  • Cis-trans isomerization
  • Doxycycline
  • Low pH
  • Tetracycline
  • TFE

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

Cite this

Molecular dynamics simulation of β 2-microglobulin in denaturing and stabilizing conditions. / Fogolari, Federico; Corazza, Alessandra; Varini, Nicola; Rotter, Matteo; Gumral, Devrim; Codutti, Luca; Rennella, Enrico; Viglino, Paolo; Bellotti, Vittorio; Esposito, Gennaro.

In: Proteins: Structure, Function and Bioinformatics, Vol. 79, No. 3, 01.03.2011, p. 986-1001.

Research output: Contribution to journalArticle

Fogolari, F, Corazza, A, Varini, N, Rotter, M, Gumral, D, Codutti, L, Rennella, E, Viglino, P, Bellotti, V & Esposito, G 2011, 'Molecular dynamics simulation of β 2-microglobulin in denaturing and stabilizing conditions', Proteins: Structure, Function and Bioinformatics, vol. 79, no. 3, pp. 986-1001. https://doi.org/10.1002/prot.22940
Fogolari, Federico ; Corazza, Alessandra ; Varini, Nicola ; Rotter, Matteo ; Gumral, Devrim ; Codutti, Luca ; Rennella, Enrico ; Viglino, Paolo ; Bellotti, Vittorio ; Esposito, Gennaro. / Molecular dynamics simulation of β 2-microglobulin in denaturing and stabilizing conditions. In: Proteins: Structure, Function and Bioinformatics. 2011 ; Vol. 79, No. 3. pp. 986-1001.
@article{a77a0e0410104d38ba2658f0bdf9ce8b,
title = "Molecular dynamics simulation of β 2-microglobulin in denaturing and stabilizing conditions",
abstract = "β 2-Microglobulin has been a model system for the study of fibril formation for 20 years. The experimental study of β 2-microglobulin structure, dynamics, and thermodynamics in solution, at atomic detail, along the pathway leading to fibril formation is difficult because the onset of disorder and aggregation prevents signal resolution in Nuclear Magnetic Resonance experiments. Moreover, it is difficult to characterize conformers in exchange equilibrium. To gain insight (at atomic level) on processes for which experimental information is available at molecular or supramolecular level, molecular dynamics simulations have been widely used in the last decade. Here, we use molecular dynamics to address three key aspects of β 2-microglobulin, which are known to be relevant to amyloid formation: (1) 60 ns molecular dynamics simulations of β 2-microglobulin in trifluoroethanol and in conditions mimicking low pH are used to study the behavior of the protein in environmental conditions that are able to trigger amyloid formation; (2) adaptive biasing force molecular dynamics simulation is used to force cis-trans isomerization at Proline 32 and to calculate the relative free energy in the folded and unfolded state. The native-like trans-conformer (known as intermediate 2 and determining the slow phase of refolding), is simulated for 10 ns, detailing the possible link between cis-trans isomerization and conformational disorder; (3) molecular dynamics simulation of highly concentrated doxycycline (a molecule able to suppress fibril formation) in the presence of β 2-microglobulin provides details of the binding modes of the drug and a rationale for its effect.",
keywords = "Cis-trans isomerization, Doxycycline, Low pH, Tetracycline, TFE",
author = "Federico Fogolari and Alessandra Corazza and Nicola Varini and Matteo Rotter and Devrim Gumral and Luca Codutti and Enrico Rennella and Paolo Viglino and Vittorio Bellotti and Gennaro Esposito",
year = "2011",
month = "3",
day = "1",
doi = "10.1002/prot.22940",
language = "English (US)",
volume = "79",
pages = "986--1001",
journal = "Proteins: Structure, Function and Genetics",
issn = "0887-3585",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - Molecular dynamics simulation of β 2-microglobulin in denaturing and stabilizing conditions

AU - Fogolari, Federico

AU - Corazza, Alessandra

AU - Varini, Nicola

AU - Rotter, Matteo

AU - Gumral, Devrim

AU - Codutti, Luca

AU - Rennella, Enrico

AU - Viglino, Paolo

AU - Bellotti, Vittorio

AU - Esposito, Gennaro

PY - 2011/3/1

Y1 - 2011/3/1

N2 - β 2-Microglobulin has been a model system for the study of fibril formation for 20 years. The experimental study of β 2-microglobulin structure, dynamics, and thermodynamics in solution, at atomic detail, along the pathway leading to fibril formation is difficult because the onset of disorder and aggregation prevents signal resolution in Nuclear Magnetic Resonance experiments. Moreover, it is difficult to characterize conformers in exchange equilibrium. To gain insight (at atomic level) on processes for which experimental information is available at molecular or supramolecular level, molecular dynamics simulations have been widely used in the last decade. Here, we use molecular dynamics to address three key aspects of β 2-microglobulin, which are known to be relevant to amyloid formation: (1) 60 ns molecular dynamics simulations of β 2-microglobulin in trifluoroethanol and in conditions mimicking low pH are used to study the behavior of the protein in environmental conditions that are able to trigger amyloid formation; (2) adaptive biasing force molecular dynamics simulation is used to force cis-trans isomerization at Proline 32 and to calculate the relative free energy in the folded and unfolded state. The native-like trans-conformer (known as intermediate 2 and determining the slow phase of refolding), is simulated for 10 ns, detailing the possible link between cis-trans isomerization and conformational disorder; (3) molecular dynamics simulation of highly concentrated doxycycline (a molecule able to suppress fibril formation) in the presence of β 2-microglobulin provides details of the binding modes of the drug and a rationale for its effect.

AB - β 2-Microglobulin has been a model system for the study of fibril formation for 20 years. The experimental study of β 2-microglobulin structure, dynamics, and thermodynamics in solution, at atomic detail, along the pathway leading to fibril formation is difficult because the onset of disorder and aggregation prevents signal resolution in Nuclear Magnetic Resonance experiments. Moreover, it is difficult to characterize conformers in exchange equilibrium. To gain insight (at atomic level) on processes for which experimental information is available at molecular or supramolecular level, molecular dynamics simulations have been widely used in the last decade. Here, we use molecular dynamics to address three key aspects of β 2-microglobulin, which are known to be relevant to amyloid formation: (1) 60 ns molecular dynamics simulations of β 2-microglobulin in trifluoroethanol and in conditions mimicking low pH are used to study the behavior of the protein in environmental conditions that are able to trigger amyloid formation; (2) adaptive biasing force molecular dynamics simulation is used to force cis-trans isomerization at Proline 32 and to calculate the relative free energy in the folded and unfolded state. The native-like trans-conformer (known as intermediate 2 and determining the slow phase of refolding), is simulated for 10 ns, detailing the possible link between cis-trans isomerization and conformational disorder; (3) molecular dynamics simulation of highly concentrated doxycycline (a molecule able to suppress fibril formation) in the presence of β 2-microglobulin provides details of the binding modes of the drug and a rationale for its effect.

KW - Cis-trans isomerization

KW - Doxycycline

KW - Low pH

KW - Tetracycline

KW - TFE

UR - http://www.scopus.com/inward/record.url?scp=79551496525&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79551496525&partnerID=8YFLogxK

U2 - 10.1002/prot.22940

DO - 10.1002/prot.22940

M3 - Article

C2 - 21287627

AN - SCOPUS:79551496525

VL - 79

SP - 986

EP - 1001

JO - Proteins: Structure, Function and Genetics

JF - Proteins: Structure, Function and Genetics

SN - 0887-3585

IS - 3

ER -