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A comparative study of HIV-1 and HTLV-I protease structure and dynamics reveals a conserved residue interaction network

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Abstract

The two retroviruses human T-lymphotropic virus type I (HTLV-I) and human immunodeficiency virus type 1 (HIV-1) are the causative agents of severe and fatal diseases including adult T-cell leukemia and the acquired immune deficiency syndrome (AIDS). Both viruses code for a protease that is essential for replication and therefore represents a key target for drugs interfering with viral infection. The retroviral proteases from HIV-1 and HTLV-I share 31% sequence identity and high structural similarities. Yet, their substrate specificities and inhibition profiles differ substantially. In this study, we performed all-atom molecular dynamics (MD) simulations for both enzymes in their ligand-free states and in complex with model substrates in order to compare their dynamic behaviors and enhance our understanding of the correlation between sequence, structure, and dynamics in this protein family. We found extensive similarities in both local and overall protein dynamics, as well as in the energetics of their interactions with model substrates. Interestingly, those residues that are important for strong ligand binding are frequently not conserved in sequence, thereby offering an explanation for the differences in binding specificity. Moreover, we identified an interaction network of contacts between conserved residues that interconnects secondary structure elements and serves as a scaffold for the protein fold. This interaction network is conformationally stable over time and may provide an explanation for the highly similar dynamic behavior of the two retroviral proteases, even in the light of their rather low overall sequence identity.

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Abbreviations

ATL:

Adult T-cell leukemia

CA/NC cleavage site:

Protease cleavage site in HTLV-I polyprotein precursor between the capsid and nucleocapsid proteins

HIV-PR:

HIV-1 protease

HTLV-PR:

HTLV-I protease

MA/CA cleavage site:

Protease cleavage site in HIV-1 and HTLV-I polyprotein precursors between the matrix and capsid proteins

MD:

Molecular dynamics

p2/NC cleavage site:

Protease cleavage site in HIV-1 polyprotein precursor between the p2 and nucleocapsid proteins

PDB:

Protein Data Bank

RMSF:

Root-mean-square fluctuation

TSP/HAM:

Tropical spastic paraparesis

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Acknowledgments

The authors thank the Regionales Rechenzentrum Erlangen (RRZE) for technical support and the Deutsche Forschungsgemeinschaft (graduate program GRK1071) for funding.

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  1. Bioinformatik, Institut für Biochemie and Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054, Erlangen, Germany

    Pia Rücker, Anselm H. C. Horn, Heike Meiselbach & Heinrich Sticht

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  1. Pia Rücker
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  2. Anselm H. C. Horn
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  3. Heike Meiselbach
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  4. Heinrich Sticht
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Correspondence to Heinrich Sticht.

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ESM 1

A plot showing the potential energy as a function of the simulation time, and a graph of the van der Waals and electrostatic interaction energies of HTLV-PR with its model substrate (PDF 346 kb)

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Rücker, P., Horn, A.H.C., Meiselbach, H. et al. A comparative study of HIV-1 and HTLV-I protease structure and dynamics reveals a conserved residue interaction network. J Mol Model 17, 2693–2705 (2011). https://doi.org/10.1007/s00894-011-0971-1

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