Abstract
The efficiency of protease inhibiting drugs is hampered by the rapid emergence of protease variants. Understanding this phenomenon requires the characterization of the salient steps of HIV-1 protease's catalytic cycle. We summarize our investigations on the reactive geometry of the protease-substrate complex based on first principles, QM/MM and classical atomistic molecular dynamics simulations. Previous and novel analysis indicates that the reactive geometry is assisted by a mechanical coupling between the local structural fluctuations at the active site and large scale-motion of the entire protein. Additional coarse-grained modeling further allows uncovering unexpected analogies of concerted large-scale movements across members of the aspartyl-protease family. Taken together, these results may help understand some aspects of the resistance against drugs targeting HIV-1 protease. We further present computational studies on HIV-1 transactivator of transcription (Tot) viral RNA binding protein. Interfering with Tat/TAR interactions is a promising strategy for anti-AIDS intervention. We have identified conserved structural and energetic features among different protein isolates and predicted the structural determinants of Tat in complex with one of the host cell cognate proteins, p/CAF. These findings may help the design of ligands interfering with Tat function.
| Original language | English |
|---|---|
| Pages (from-to) | 97-105 |
| Number of pages | 9 |
| Journal | Journal of Molecular Structure: THEOCHEM |
| Volume | 898 |
| Issue number | 1-3 |
| DOIs | |
| Publication status | Published - Mar 30 2009 |
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Keywords
- Bioinformatics
- Coarse-grained
- DFT
- MD simulations
- QM/MM
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Biochemistry
- Condensed Matter Physics
Cite this
Multi-scale modeling of HIV-1 proteins. / Carnevale, Vincenzo; Raugei, Simone; Neri, Marilisa; Pantano, Sergio; Micheletti, Cristian; Carloni, Paolo.
In: Journal of Molecular Structure: THEOCHEM, Vol. 898, No. 1-3, 30.03.2009, p. 97-105.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Multi-scale modeling of HIV-1 proteins
AU - Carnevale, Vincenzo
AU - Raugei, Simone
AU - Neri, Marilisa
AU - Pantano, Sergio
AU - Micheletti, Cristian
AU - Carloni, Paolo
PY - 2009/3/30
Y1 - 2009/3/30
N2 - The efficiency of protease inhibiting drugs is hampered by the rapid emergence of protease variants. Understanding this phenomenon requires the characterization of the salient steps of HIV-1 protease's catalytic cycle. We summarize our investigations on the reactive geometry of the protease-substrate complex based on first principles, QM/MM and classical atomistic molecular dynamics simulations. Previous and novel analysis indicates that the reactive geometry is assisted by a mechanical coupling between the local structural fluctuations at the active site and large scale-motion of the entire protein. Additional coarse-grained modeling further allows uncovering unexpected analogies of concerted large-scale movements across members of the aspartyl-protease family. Taken together, these results may help understand some aspects of the resistance against drugs targeting HIV-1 protease. We further present computational studies on HIV-1 transactivator of transcription (Tot) viral RNA binding protein. Interfering with Tat/TAR interactions is a promising strategy for anti-AIDS intervention. We have identified conserved structural and energetic features among different protein isolates and predicted the structural determinants of Tat in complex with one of the host cell cognate proteins, p/CAF. These findings may help the design of ligands interfering with Tat function.
AB - The efficiency of protease inhibiting drugs is hampered by the rapid emergence of protease variants. Understanding this phenomenon requires the characterization of the salient steps of HIV-1 protease's catalytic cycle. We summarize our investigations on the reactive geometry of the protease-substrate complex based on first principles, QM/MM and classical atomistic molecular dynamics simulations. Previous and novel analysis indicates that the reactive geometry is assisted by a mechanical coupling between the local structural fluctuations at the active site and large scale-motion of the entire protein. Additional coarse-grained modeling further allows uncovering unexpected analogies of concerted large-scale movements across members of the aspartyl-protease family. Taken together, these results may help understand some aspects of the resistance against drugs targeting HIV-1 protease. We further present computational studies on HIV-1 transactivator of transcription (Tot) viral RNA binding protein. Interfering with Tat/TAR interactions is a promising strategy for anti-AIDS intervention. We have identified conserved structural and energetic features among different protein isolates and predicted the structural determinants of Tat in complex with one of the host cell cognate proteins, p/CAF. These findings may help the design of ligands interfering with Tat function.
KW - Bioinformatics
KW - Coarse-grained
KW - DFT
KW - MD simulations
KW - QM/MM
UR - http://www.scopus.com/inward/record.url?scp=60749129164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=60749129164&partnerID=8YFLogxK
U2 - 10.1016/j.theochem.2008.11.028
DO - 10.1016/j.theochem.2008.11.028
M3 - Article
VL - 898
SP - 97
EP - 105
JO - Computational and Theoretical Chemistry
JF - Computational and Theoretical Chemistry
SN - 2210-271X
IS - 1-3
ER -