Flexibility of BIV TAR-Tat: Models of Peptide Binding

Hsieh, Mark; Collins, Elaine D.; Blomquist, Thomas M.; Lustig, Brooke

doi:10.1080/07391102.2002.10506840

Cited by 5 publications

(11 citation statements)

References 27 publications

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“…The reasoning behind this is the absence of side chain optimization, where we assumed the same lattice contact frequencies for all types of Tat species. This contact map also confirmed that our newly rewritten code generates the identical output as the former program, thus validating our approach(Hsieh, M.; Lustig, B. San Jose State University. Unpublished Data.…”

supporting

confidence: 79%

“…In this thesis, the BIV TAR RNA and Tat peptide sequences were adapted from Puglisi, and other groups (Puglisi et al, 1995;Hsieh et al, 2002). nucleotides presented by their O3' atoms.…”

Section: Setting Upmentioning

confidence: 99%

“…In addition, there is no evidence of nucleotide-amino acid contact at 78 as shown by averaged NMR structures (Puglisi et al, 1995;Ye et al, 1995). However, it is worth noting that RMSD analysis of CA shows that there are possible alternate configurations whose 78 positions can have contacts with the TAR RNA (Hsieh et al, 2002). The next sections in this chapter attempt to investigate some possibilities of Gly and related flexibility effects at peptide 75 and 78 positions.…”

Section: Special Configurationsmentioning

confidence: 99%

“…higher flexibility vs. lower flexibility. Note that values less than -0.60 kcal/mol indicate increasing binding stabilization (Hsieh et al, 2002).…”

Section: Flexibility Effectsmentioning

confidence: 99%

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BIV TAR RNA Binding Glycine Mutant Tat Peptides

Nguyen

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Interactions between viral encoded regulatory proteins and RNA target sequences control gene expression of Lentiviruses, including human immunodeficiency virus (HIV). Bovine immunodeficiency virus (BIV) provides a simpler model of interaction between the viral trans-activating protein (Tat) and trans-activation response RNA element (TAR), using Tat peptides binding to TAR RNA fragments. The resulting characterization of the hinge region of native BIV TAR-Tat complex was confirmed by more comprehensive calculations, involving an exhaustive generation of lattice chains. This modeled 2-residues per move of the native 11-mer Tat peptide and a 28-nucleotides TAR fragment. But these sorts of coarse-grained calculations, upon substitution of Gly at key hinge region positions, are not fully sensitive to the local flexibility of amino acid side chains optimized for packing and possible interaction with relevant all-atom RNA structure. An overall binding destabilization effect is indicated for the single substitution at 78 and double substitution of Gly at positions 75 and 78. Destabilization effects were further examined, and model data showed that it included both potential and flexibility effects. Future studies require 1-residue per move approach and building all-atom models to fully examine molecular interactions of TAR-Tat complexes. v ACKNOWLEDGEMENTS There are three main individuals whom I would like to offer my deep gratitude for helping m throughout my time at the Department of Chemistry at San Jose State University. First and foremost, I would like to thank Dr. Brooke Lustig, my research advisor, for mentoring me during my research projects and the writing of my Masters thesis. He provided me with his patience, knowledge, and expertise for the completion of this project. Most importantly, he gave me a chance to become a more scientific, logical, and critical thinker, which will definitely be helpful for my next career journey. I would also like to thank my committee members, Dr. Lionel Cheruzel and Dr. Elaine D. Collins, for taking the time to review my thesis. I especially would like to thank Dr. Cheruzel for putting up with me and giving me great advice. I would like to thank Savitha Srnivasan, a former graduate student at Dr. Lustig's lab for her help during my first time in the lab. I would also like to thank the undergraduate students, Reema Shalan, Lilley Tran, and Ashleen Kaur for assisting me throughout the project. For my family, I would like to thank my parents for their financial support. I am also extremely grateful to Hong Nguyen, my fiancée, who has been absolutely patient, encouraging, and my pillar of mental support throughout my academic years. With her unconditional love and unshakable support over the years, we manage to pull through the hard times and stay strong together. Last but not least, this thesis is dedicated to my loving and caring grandfather in heaven. To others who have been supporting me, I thank you very much.

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supporting

confidence: 79%

“…In this thesis, the BIV TAR RNA and Tat peptide sequences were adapted from Puglisi, and other groups (Puglisi et al, 1995;Hsieh et al, 2002). nucleotides presented by their O3' atoms.…”

Section: Setting Upmentioning

confidence: 99%

Section: Special Configurationsmentioning

confidence: 99%

“…higher flexibility vs. lower flexibility. Note that values less than -0.60 kcal/mol indicate increasing binding stabilization (Hsieh et al, 2002).…”

Section: Flexibility Effectsmentioning

confidence: 99%

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BIV TAR RNA Binding Glycine Mutant Tat Peptides

Nguyen

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“…Without trans-activation, the polymerase produces primarily short transcripts and viral replication is disrupted 4, 5 . Extensive structural studies of TAR RNA have paved the way for the design of molecules to compete with the Tat protein in binding to the TAR element, thus inhibiting viral replication 3, 6–19 . However, to date none of these efforts have yielded leads with the potency and specificity required for successful clinical candidacy.…”

Section: Introductionmentioning

confidence: 99%

A Small-Molecule Probe Induces a Conformation in HIV TAR RNA Capable of Binding Drug-Like Fragments

Davidson

Begley

Lau

et al. 2011

Journal of Molecular Biology

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The HIV-1 TAR/Tat interaction is a potentially valuable target for treating HIV infection, but efforts to develop TAR-binding antiviral drugs have not yet yielded a successful candidate for clinical development. In this work, we describe a novel approach towards screening fragments against RNA that uses a chemical probe to target the Tat binding region of TAR. This probe fulfills two critical roles in the screen: by locking the RNA into a conformation capable of binding other fragments, it simultaneously allows the identification of proximal binding fragments by ligand-based NMR. Using this approach, we have discovered six novel TAR-binding fragments, three of which were docked relative to the probe/RNA structure using experimental NMR restraints. The consistent orientations of functional groups in our data-driven docked structures and common electrostatic properties across all fragment leads reveal a surprising level of selectivity by our fragment-sized screening hits. These models further suggest linking strategies for the development of higher affinity lead compounds for the inhibition of the TAR/Tat interaction.

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Correlation in Domain Fluctuations Navigates Target Search of a Viral Peptide along RNA

et al. 2021

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Biological macromolecules often exhibit correlations in fluctuations involving distinct domains. This study decodes their functional implications in RNA–protein recognition and target-specific binding. The target search of a peptide along RNA in a viral TAR–Tat complex is closely monitored using atomistic simulations, steered molecular dynamics simulations, free energy calculations, and a machine-learning-based clustering technique. An anticorrelated domain fluctuation is identified between the tetraloop and the bulge region in the apo form of TAR RNA that sets a hierarchy in the domain-specific fluctuations at each binding event and that directs the succeeding binding footsteps. Thus, at each binding footstep, the dynamic partner selects an RNA location for binding where it senses a higher fluctuation, which is conventionally reduced upon binding. This event stimulates an alternate domain fluctuation, which then dictates sequential binding footstep/s and thus the search progresses. Our cross-correlation maps show that the fluctuations relay from one domain to another specific domain until the anticorrelation between those interdomain fluctuations sustains. Artificial attenuation of that hierarchical domain fluctuation inhibits specific RNA binding. The binding is completed with the arrival of a few long-lived water molecules that mediate slightly distant RNA–protein sites and finally stabilize the overall complex. The study underscores the functional importance of naturally designed fluctuating RNA motifs (bulge, tetraloop) and their interplay in dictating the directionality of the search in a highly dynamic environment.

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Flexibility of BIV TAR-Tat: Models of Peptide Binding

Cited by 5 publications

References 27 publications

BIV TAR RNA Binding Glycine Mutant Tat Peptides

BIV TAR RNA Binding Glycine Mutant Tat Peptides

A Small-Molecule Probe Induces a Conformation in HIV TAR RNA Capable of Binding Drug-Like Fragments

Correlation in Domain Fluctuations Navigates Target Search of a Viral Peptide along RNA

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