Computational study of bindings of HL9, a nonapeptide fragment of human lysozyme, to HIV-1 fusion protein gp41

Hartono, Yossa Dwi; Lee, Angelina Noviani; Lee‐Huang, Sylvia; Zhang, Dawei

doi:10.1016/j.bmcl.2011.01.121

Cited by 20 publications

(15 citation statements)

References 23 publications

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“…During such sequence of conformational change of gp41, several targets for antibodies and anti‐HIV drugs are accessible. Much has been said about the highly conserved hydrophobic binding pocket on NHR, targeted by antibodies D5, DN9, 8K8, and HK20,3–5 as well as Roche's fusion inhibitor enfuvirtide,6 human lysozyme, and the latter's peptide derivatives HL18 and HL9 7, 8. Another region of gp41, the Trp‐rich membrane‐proximal ectodomain region (MPER), has been found to elicit responses from monoclonal antibodies 2F5, 4E10, and Z13 9–11.…”

Section: Introductionmentioning

confidence: 99%

“…Much has been said about the highly conserved hydrophobic binding pocket on NHR, targeted by antibodies D5, DN9, 8K8, and HK20, 3-5 as well as Roche's fusion inhibitor enfuvirtide, 6 human lysozyme, and the latter's peptide derivatives HL18 and HL9. 7,8 Another region of gp41, the Trp-rich membrane-proximal ectodomain region (MPER), has been found to elicit responses from monoclonal antibodies 2F5, 4E10, and Z13. 9-11 MPER is located at the base of gp41, proximal to the viral membrane and gp41 transmembrane region, hence its name.…”

Section: Introductionmentioning

confidence: 99%

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Adsorption and folding dynamics of MPER of HIV‐1 gp41 in the presence of dpc micelle

2013

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Membrane-proximal ectodomain region (MPER) of HIV-1 gp41 is known to have several epitopes of monoclonal antibodies. It also plays an important role in the membrane fusion process that is well-evidenced, though not well-elucidated. There are also disputes over the true structure of MPER. In this study, MPER NMR structure in the presence of dodecylphosphatidylcholine micelle is used in the molecular dynamic simulation to elucidate structural dynamics and adsorption to model MPER interaction in a membrane environment. Polarized protein-specific charge derived from its NMR structure is found to better preserve the helical structure found in the NMR structure compared to AMBER03 calculation. The preserved helical structure also adsorb to the micelle using the hydrophobic side-chains, consistent to the NMR structure. Ab initio folding of MPER predicts a structure quite in well agreement with the NMR structure (RMSd 3.9 Å) and shows that the micelle plays a role in the folding process.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adsorption and folding dynamics of MPER of HIV‐1 gp41 in the presence of dpc micelle

2013

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“…The SIE function has also been applied retrospectively as well as prospectively in several other independent laboratories that have reported SIE predictions versus actual binding affinities [18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Collectively, these data indicate an MUE of 1.30 kcal/mol and an r 2 of 0.47 between the predicted and actual absolute binding affinities (Fig.…”

Section: Published Studiesmentioning

confidence: 81%

“…Calibration of several physical parameters, including the dielectric constant, Born radii, surface tension coefficient, and enthalpy-entropy compensation scaling factor, was based on a diverse dataset of 99 protein-ligand complexes [15]. The SIE scoring function parametrized in this manner achieves a reasonable transferability across a wide variety of protein-ligand systems, consistently returning absolute binding affinities within the experimental range, as demonstrated by test cases published in the literature [18][19][20][21][22][23][24][25][26][27][28][29][30][31]. External testing of the standard SIE parametrization in the CSAR-2010 scoring challenge consisting in a curated dataset of 343 protein-ligand complexes diverse with respect to ligands and targets [32,33], afforded binding affinity predictions with a mean-unsigned-error (MUE) of about 2 kcal/mol [34].…”

Section: Introductionmentioning

confidence: 99%

Exhaustive search and solvated interaction energy (SIE) for virtual screening and affinity prediction

Sulea

Hogues

Purisima

2011

J Comput Aided Mol Des

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We carried out a prospective evaluation of the utility of the SIE (solvation interaction energy) scoring function for virtual screening and binding affinity prediction. Since experimental structures of the complexes were not provided, this was an exercise in virtual docking as well. We used our exhaustive docking program, Wilma, to provide high-quality poses that were rescored using SIE to provide binding affinity predictions. We also tested the combination of SIE with our latest solvation model, first shell of hydration (FiSH), which captures some of the discrete properties of water within a continuum model. We achieved good enrichment in virtual screening of fragments against trypsin, with an area under the curve of about 0.7 for the receiver operating characteristic curve. Moreover, the early enrichment performance was quite good with 50% of true actives recovered with a 15% false positive rate in a prospective calculation and with a 3% false positive rate in a retrospective application of SIE with FiSH. Binding affinity predictions for both trypsin and host-guest complexes were generally within 2 kcal/mol of the experimental values. However, the rank ordering of affinities differing by 2 kcal/mol or less was not well predicted. On the other hand, it was encouraging that the incorporation of a more sophisticated solvation model into SIE resulted in better discrimination of true binders from binders. This suggests that the inclusion of proper Physics in our models is a fruitful strategy for improving the reliability of our binding affinity predictions.

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“…For example, human lysozyme has been shown to inhibit HIV-1 infection in vitro by preventing the adsorption and penetration of the virus (62, 63). HL9, a nonapeptide fragment of human lysozyme, blocks HIV-1 viral entrance and replication by binding to the ectodomain of gp41, the envelope glycoprotein of HIV-1 crucial to membrane fusion (63, 64). These data strongly suggest that ALF and LYZ family have effective antiviral activity, and it seems reasonable to hypothesize that shrimp ALF and LYZ family are able to interact with WSSV structural proteins.…”

Section: Discussionmentioning

confidence: 99%

RNAi screening identifies a new Toll from shrimp that restricts WSSV infection through activating Dorsal to induce antimicrobial peptides

Yin

Wang

et al. 2018

Preprint

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ABSTRACT：The function of Toll pathway defense against bacterial infection has been well 37 established in shrimp, however how this pathway responds to viral infection is still largely 38 unknown. In this study, we report the Toll4-Dorsal-AMPs cascade restricts the white spot 39 syndrome virus (WSSV) infection of shrimp. A total of nine Tolls from Litopenaeus 40 vannamei namely Toll1-9 are identified, and RNAi screening in vivo reveals the Toll4 is 41 important for shrimp to oppose WSSV infection. Knockdown of Toll4 results in elevated viral 42 loads and renders shrimp more susceptible to WSSV. Furthermore, Toll4 could be a one of 43 upstream pattern recognition receptor (PRR) to detect WSSV, and thereby leading to nuclear 44 translocation and phosphorylation of Dorsal, the known NF-κB transcription factor of the 45 canonical Toll pathway. More importantly, silencing of Toll4 and Dorsal contributes to 46 impaired expression of a specific set of antimicrobial peptides (AMPs) such as 47anti-LPS-factor (ALF) and lysozyme (LYZ) family, which exert potent anti-WSSV activity. 48Two AMPs of ALF1 and LYZ1 as representatives are demonstrated to have the ability to 49 interact with several WSSV structural proteins. Taken together, we therefore identify the 50 Toll4-Dorsal pathway mediates strong resistance to WSSV infection by inducing some 51 specific AMPs. 53Author summary：The TLR pathway mediated antiviral immune response is well identified 54 in mammals, yet, Toll pathway governing this protection in invertebrates remains unknown. 55In the present study, we uncover that a shrimp Toll4 from a total of nine Tolls in L. vannamei 56 confers resistance to WSSV thought inducing the NF-κB transcription factor Dorsal to 57 inspiring the production of some antimicrobial peptides (AMPs) with antiviral activity. The 58 anti-LPS-factor (ALF) and lysozyme (LYZ) family are identified as the Toll4-Dorsal pathway 59 targeted genes with the ability to interact with viral structural proteins in response to WSSV 60 infection. These results suggest that the Toll receptor induces the expression of AMPs with 61 antiviral activity could be a general antiviral mechanism in invertebrates and Toll pathway 62 established antiviral defense could be conserved during evolution.63 KEYWORDS: Litopenaeus vannamei; Toll4-Dorsal pathway; Antiviral defense; WSSV; 64 antimicrobial peptides (AMPs) 65 66 67Multicellular organisms have evolved the ability to protect themselves from a wide 68 variety of pathogens including virus. In invertebrates including shrimps that lacking 69 immunoglobulin-based adaptive immune system, this protection is thus provided through the 70 action of an innate immune system. The innate immune response is generally initiated via the 71 detection of pathogen-associated molecular patterns (PAMPs), some evolutionarily conserved 72 structures or motifs shared by broad classes of invading organisms, by a wide diversity of 73 host pattern recognition receptors (PRRs) (1). One important class of PRRs is the Toll 74 receptor superfamily, ...

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Computational study of bindings of HL9, a nonapeptide fragment of human lysozyme, to HIV-1 fusion protein gp41

Cited by 20 publications

References 23 publications

Adsorption and folding dynamics of MPER of HIV‐1 gp41 in the presence of dpc micelle

Adsorption and folding dynamics of MPER of HIV‐1 gp41 in the presence of dpc micelle

Exhaustive search and solvated interaction energy (SIE) for virtual screening and affinity prediction

RNAi screening identifies a new Toll from shrimp that restricts WSSV infection through activating Dorsal to induce antimicrobial peptides

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