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A Molecular Dynamics Model of HIV-1 Reverse Transcriptase Complexed with DNA: Comparison with Experimental Structures

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Abstract

We have built a molecular dynamics model for human immunodeficiency virus (HIV-1) reverse transcriptase (RT) complexed with a 19/18-mer template/primer by combining the structural information of a low resolution crystal structure of a HIV-1 RT/DNA complex (1hmi) with that of a high resolution crystal structure of unliganded HIV-1 RT (1rtj). The process involved slow forcing of the α-carbons of 1rtj onto those of 1hmi using constrained MD simulations, while immersing the protein in aqueous solution. A similar technique was used to build the bent all-atom DNA duplex, which was then docked into the modeled protein. The resulting model complex was refined using molecular dynamics simulation with the Particle-mesh Ewald method employed to accommodate long-range electrostatic interactions. New parameters of the Amber force field that affect DNA twist are tested and largely validated. The model has been used successfully to explain the results of vertical scanning mutagenesis of residue 266 (Trp266). Recently, the low resolution crystal structure of the HIV-1 RT/DNA complex has been refined to a 2.8 Å resolution (2hmi) and a crystal structure of a HIV-1/RT/dTTP ternary complex has been determined at 3.2 Å resolution (1rtd). A detailed structural comparison of the prior model structure and the two experimental structures becomes possible. Overall, the three structures share many similarities. The root mean square deviations of the α-carbons for the individual subdomains among the three structures are within the same ranges. The secondary structure assignments in the three structures are nearly identical. Key protein-DNA contacts such as those in the region of the primer grip are also similar in the three structures.

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Abbreviations

1hmi:

low resolution crystal structure of a HIV-1 RT/DNA/Fab complex

2hmi:

refined crystal structure of 1hmi

1rtj:

crystal structure of a high resolution unliganded HIV-1 RT

1rtd:

crystal structure of a HIV-1 RT/DNA/dTTP ternary complex

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Correspondence to Thomas A. Darden.

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Li, L., Pedersen, L.G., Beard, W.A. et al. A Molecular Dynamics Model of HIV-1 Reverse Transcriptase Complexed with DNA: Comparison with Experimental Structures. J Mol Model 6, 575–586 (2000). https://doi.org/10.1007/s0089400060575

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  • DOI: https://doi.org/10.1007/s0089400060575

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