Molecular dynamics studies on the HIV-1 integrase catalytic domain

Roberto D. Lins; James M. Briggs; T. P. Straatsma; Heather A. Carlson; Jason Greenwald; Senyon Choe; J. Andrew McCammon

doi:10.1016/S0006-3495(99)77453-9

Molecular dynamics studies on the HIV-1 integrase catalytic domain

Roberto D. Lins, James M. Briggs, T. P. Straatsma, Heather A. Carlson, Jason Greenwald, Senyon Choe, J. Andrew McCammon

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

The HIV-1 integrase, which is essential for viral replication, catalyzes the insertion of viral DNA into the host chromosome, thereby recruiting host cell machinery into making viral proteins. It represents the third main HIV enzyme target for inhibitor design, the first two being the reverse transcriptase and the protease. Two 1-ns molecular dynamics simulations have been carried out on completely hydrated models of the HIV-1 integrase catalytic domain, one with no metal ions and another with one magnesium ion in the catalytic site. The simulations predict that the region of the active site that is missing in the published crystal structures has (at the time of this work) more secondary structure than previously thought. The flexibility of this region has been discussed with respect to the mechanistic function of the enzyme. The results of these simulations will be used as part of inhibitor design projects directed against the catalytic domain of the enzyme.

Original language	English
Pages (from-to)	2999-3011
Number of pages	13
Journal	Biophysical Journal
Volume	76
Issue number	6
DOIs	https://doi.org/10.1016/S0006-3495(99)77453-9
State	Published - Jun 1999
Externally published	Yes

Funding

Drs. Volkhard Helms, Wolfgang Weber, and Rick Bushman are acknowledged for many useful conversations and advice. HAC is grateful to the American Cancer Society for a postdoctoral fellowship (PF-4427) and also thanks the La Jolla Interfaces in Science Training Program. The authors thank the San Diego Supercomputer Center for grants of computer time (to J.M.B. and J.A.M.). Gratitude is also expressed to Molecular Simulations, Inc., San Diego, CA for generously providing us with the InsightII and Quanta software. This project is supported by the NIH Program on Structural Biology of AIDS Related Proteins (GM56553). The NWChem computational chemistry package for parallel computers used in this study was developed by the High Performance Computational Chemistry Group, Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, and funded by the Offices of Biological and Environmental Research, Computational and Technology Research, and Basic Energy Sciences in the U.S. Department of Energy. Pacific Northwestern Laboratory is operated for the U.S. Department of Energy by Battele Memorial Institute under contract ACO6_76RLO 1830.

Funders	Funder number
Battele Memorial Institute	ACO6_76RLO 1830
Biological and Environmental Research, Computational and Technology Research
NIH Program on Structural Biology of AIDS Related Proteins
U.S. Department of Energy
American Cancer Society	PF-4427
National Institute of General Medical Sciences	P01GM056553
Basic Energy Sciences
Pacific Northwest National Laboratory

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/S0006-3495(99)77453-9

Cite this

@article{7baa66aca6db4df89b655143853dec22,

title = "Molecular dynamics studies on the HIV-1 integrase catalytic domain",

abstract = "The HIV-1 integrase, which is essential for viral replication, catalyzes the insertion of viral DNA into the host chromosome, thereby recruiting host cell machinery into making viral proteins. It represents the third main HIV enzyme target for inhibitor design, the first two being the reverse transcriptase and the protease. Two 1-ns molecular dynamics simulations have been carried out on completely hydrated models of the HIV-1 integrase catalytic domain, one with no metal ions and another with one magnesium ion in the catalytic site. The simulations predict that the region of the active site that is missing in the published crystal structures has (at the time of this work) more secondary structure than previously thought. The flexibility of this region has been discussed with respect to the mechanistic function of the enzyme. The results of these simulations will be used as part of inhibitor design projects directed against the catalytic domain of the enzyme.",

author = "Lins, {Roberto D.} and Briggs, {James M.} and Straatsma, {T. P.} and Carlson, {Heather A.} and Jason Greenwald and Senyon Choe and McCammon, {J. Andrew}",

year = "1999",

month = jun,

doi = "10.1016/S0006-3495(99)77453-9",

language = "English",

volume = "76",

pages = "2999--3011",

journal = "Biophysical Journal",

issn = "0006-3495",

publisher = "Biophysical Society",

number = "6",

}

TY - JOUR

T1 - Molecular dynamics studies on the HIV-1 integrase catalytic domain

AU - Lins, Roberto D.

AU - Briggs, James M.

AU - Straatsma, T. P.

AU - Carlson, Heather A.

AU - Greenwald, Jason

AU - Choe, Senyon

AU - McCammon, J. Andrew

PY - 1999/6

Y1 - 1999/6

N2 - The HIV-1 integrase, which is essential for viral replication, catalyzes the insertion of viral DNA into the host chromosome, thereby recruiting host cell machinery into making viral proteins. It represents the third main HIV enzyme target for inhibitor design, the first two being the reverse transcriptase and the protease. Two 1-ns molecular dynamics simulations have been carried out on completely hydrated models of the HIV-1 integrase catalytic domain, one with no metal ions and another with one magnesium ion in the catalytic site. The simulations predict that the region of the active site that is missing in the published crystal structures has (at the time of this work) more secondary structure than previously thought. The flexibility of this region has been discussed with respect to the mechanistic function of the enzyme. The results of these simulations will be used as part of inhibitor design projects directed against the catalytic domain of the enzyme.

AB - The HIV-1 integrase, which is essential for viral replication, catalyzes the insertion of viral DNA into the host chromosome, thereby recruiting host cell machinery into making viral proteins. It represents the third main HIV enzyme target for inhibitor design, the first two being the reverse transcriptase and the protease. Two 1-ns molecular dynamics simulations have been carried out on completely hydrated models of the HIV-1 integrase catalytic domain, one with no metal ions and another with one magnesium ion in the catalytic site. The simulations predict that the region of the active site that is missing in the published crystal structures has (at the time of this work) more secondary structure than previously thought. The flexibility of this region has been discussed with respect to the mechanistic function of the enzyme. The results of these simulations will be used as part of inhibitor design projects directed against the catalytic domain of the enzyme.

UR - http://www.scopus.com/inward/record.url?scp=0033063512&partnerID=8YFLogxK

U2 - 10.1016/S0006-3495(99)77453-9

DO - 10.1016/S0006-3495(99)77453-9

M3 - Article

C2 - 10354426

AN - SCOPUS:0033063512

SN - 0006-3495

VL - 76

SP - 2999

EP - 3011

JO - Biophysical Journal

JF - Biophysical Journal

IS - 6

ER -

Molecular dynamics studies on the HIV-1 integrase catalytic domain

Abstract

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this