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Mechanism of action of cyclophilin a explored by metadynamics simulations.

Leone V, Lattanzi G, Molteni C, Carloni P - PLoS Comput. Biol. (2009)

Bottom Line: Trans/cis prolyl isomerisation is involved in several biological processes, including the development of numerous diseases.In the HIV-1 capsid protein (CA), such a process takes place in the uncoating and recruitment of the virion and is catalyzed by cyclophilin A (CypA).Our results allow us to propose a novel mechanistic hypothesis, which is finally consistent with all of the available molecular biology data.

View Article: PubMed Central - PubMed

Affiliation: International School for Advanced Studies (SISSA), Trieste, Italy.

ABSTRACT
Trans/cis prolyl isomerisation is involved in several biological processes, including the development of numerous diseases. In the HIV-1 capsid protein (CA), such a process takes place in the uncoating and recruitment of the virion and is catalyzed by cyclophilin A (CypA). Here, we use metadynamics simulations to investigate the isomerization of CA's model substrate HAGPIA in water and in its target protein CypA. Our results allow us to propose a novel mechanistic hypothesis, which is finally consistent with all of the available molecular biology data.

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Related in: MedlinePlus

PEPT-WAT.Free energy (kcal/mol) of the /HAGPIA/ peptide in solution as a function of the dihedral angles ζ and ψ (in degrees, showed in the inset). The plot is divided in transition and minima regions, with representative structures (center of the lower free energy cluster within each minima and TS region) for each region explicitly shown (See Text S1 for details), along with water molecules within a shell of 2 Å (red spheres).
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pcbi-1000309-g004: PEPT-WAT.Free energy (kcal/mol) of the /HAGPIA/ peptide in solution as a function of the dihedral angles ζ and ψ (in degrees, showed in the inset). The plot is divided in transition and minima regions, with representative structures (center of the lower free energy cluster within each minima and TS region) for each region explicitly shown (See Text S1 for details), along with water molecules within a shell of 2 Å (red spheres).

Mentions: The free energy profile plot shows that the trans0 conformer, in which ζ∼±180° and ψ∼0°, is the absolute minimum (Figure 4 and Table 2). The second trans minimum is trans180 (ζ∼±180° and ψ∼±180°), whose free energy is higher by 3 kcal/mol (Table 2, Table 3), possibly because the P4N forms a H-bond to the amide group of the adjacent residue only in trans0 (Table S3, see Figure 2 and Figure 1 for atom labelling).


Mechanism of action of cyclophilin a explored by metadynamics simulations.

Leone V, Lattanzi G, Molteni C, Carloni P - PLoS Comput. Biol. (2009)

PEPT-WAT.Free energy (kcal/mol) of the /HAGPIA/ peptide in solution as a function of the dihedral angles ζ and ψ (in degrees, showed in the inset). The plot is divided in transition and minima regions, with representative structures (center of the lower free energy cluster within each minima and TS region) for each region explicitly shown (See Text S1 for details), along with water molecules within a shell of 2 Å (red spheres).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2643488&req=5

pcbi-1000309-g004: PEPT-WAT.Free energy (kcal/mol) of the /HAGPIA/ peptide in solution as a function of the dihedral angles ζ and ψ (in degrees, showed in the inset). The plot is divided in transition and minima regions, with representative structures (center of the lower free energy cluster within each minima and TS region) for each region explicitly shown (See Text S1 for details), along with water molecules within a shell of 2 Å (red spheres).
Mentions: The free energy profile plot shows that the trans0 conformer, in which ζ∼±180° and ψ∼0°, is the absolute minimum (Figure 4 and Table 2). The second trans minimum is trans180 (ζ∼±180° and ψ∼±180°), whose free energy is higher by 3 kcal/mol (Table 2, Table 3), possibly because the P4N forms a H-bond to the amide group of the adjacent residue only in trans0 (Table S3, see Figure 2 and Figure 1 for atom labelling).

Bottom Line: Trans/cis prolyl isomerisation is involved in several biological processes, including the development of numerous diseases.In the HIV-1 capsid protein (CA), such a process takes place in the uncoating and recruitment of the virion and is catalyzed by cyclophilin A (CypA).Our results allow us to propose a novel mechanistic hypothesis, which is finally consistent with all of the available molecular biology data.

View Article: PubMed Central - PubMed

Affiliation: International School for Advanced Studies (SISSA), Trieste, Italy.

ABSTRACT
Trans/cis prolyl isomerisation is involved in several biological processes, including the development of numerous diseases. In the HIV-1 capsid protein (CA), such a process takes place in the uncoating and recruitment of the virion and is catalyzed by cyclophilin A (CypA). Here, we use metadynamics simulations to investigate the isomerization of CA's model substrate HAGPIA in water and in its target protein CypA. Our results allow us to propose a novel mechanistic hypothesis, which is finally consistent with all of the available molecular biology data.

Show MeSH
Related in: MedlinePlus