Ab initio prediction of specific phospholipid complexes and membrane association of HIV-1 MPER antibodies by multi-scale simulations DOI Open Access
Colleen Maillie, Jay Golden, Ian A. Wilson

et al.

Published: Aug. 25, 2023

A potent class of HIV-1 broadly neutralizing antibodies (bnAbs) targets the envelope glycoprotein's membrane proximal exposed region (MPER) through a proposed mechanism where hypervariable loops embed into lipid bilayers and engage headgroup moieties alongside epitope. We address feasibility determinant molecular features this using multi-scale modeling. All-atom simulations 4E10, PGZL1, 10E8, LN01 docked onto HIV-like membranes consistently form phospholipid complexes at key complementarity-determining loop sites, solidifying that stable specific interactions anchor bnAbs to surfaces. Ancillary protein-lipid contacts reveal surprising contributions from antibody framework regions. Coarse-grained effectively capture embedding membranes. Simulations estimating protein-membrane interaction strength for PGZL1 variants along an inferred maturation pathway show bilayer affinity is evolved correlates with neutralization potency. The modeling demonstrated here uncovers insights participation in antibodies' recognition proteins highlights prioritize vaccine design.

Language: Английский

Ab initio prediction of specific phospholipid complexes and membrane association of HIV-1 MPER antibodies by multi-scale simulations DOI Creative Commons
Colleen Maillie,

Kiana Golden,

Ian A. Wilson

et al.

eLife, Journal Year: 2025, Volume and Issue: 12

Published: April 7, 2025

A potent class of HIV-1 broadly neutralizing antibodies (bnAbs) targets the envelope glycoprotein’s membrane proximal exposed region (MPER) through a proposed mechanism where hypervariable loops embed into lipid bilayers and engage headgroup moieties alongside epitope. We address feasibility determinant molecular features this using multi-scale modeling. All-atom simulations 4E10, PGZL1, 10E8, LN01 docked onto HIV-like membranes consistently form phospholipid complexes at key complementarity-determining loop sites, solidifying that stable specific interactions anchor bnAbs to surfaces. Ancillary protein-lipid contacts reveal surprising contributions from antibody framework regions. Coarse-grained effectively capture embedding membranes. Simulations estimating protein-membrane interaction strength for PGZL1 variants along an inferred maturation pathway show bilayer affinity is evolved correlates with neutralization potency. The modeling demonstrated here uncovers insights participation in antibodies’ recognition proteins highlights prioritize vaccine design.

Language: Английский

Citations

0
Distinctive Membrane Accommodation Traits Underpinning the Neutralization Activity of HIV-1 Antibody against MPER DOI Creative Commons
Cármen Domene, Brian Wiley, Sara Insausti

et al.

Molecular Pharmaceutics, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

The membrane-proximal external region (MPER), located in the carboxy-terminal section of HIV's envelope glycoprotein (Env) ectodomain, which is essential for viral entry into host cells, has gained considerable attention as a target HIV vaccine development due to exceptional neutralization breadth antibodies against MPER epitopes. A distinctive feature broadly neutralizing (bnAbs) targeting their requirement accommodate membrane surface antigen-binding fragment, or Fab moiety, optimize antigen recognition. In this study, we sought elucidate molecular mechanism behind interaction and its relevance antiviral function bnAb 10E8. We conducted all-atom dynamics simulations three systems: (i) 10E8 positioned on viral-like lipid bilayer (VL-LB), (ii) complex with an helix anchored VL-LB via Env transmembrane domain (TMD), (iii) Fab/MPER-TMD similarly embedded but chemically optimized variant showing enhanced potency. Comparing these systems enabled us derive atomic-scale Fab-membrane accommodation profiles pertinent 10E8's function. Our findings support that adaptation interface following epitope binding crucial developing MPER-targeted activity. This analysis also provides insights pathways strengthening interactions, may prove valuable designing MPER-based biologics vaccines prevent treat infection.

Language: Английский

Citations

0
Generation of a Nonbilayer Lipid Nanoenvironment after Epitope Binding Potentiates Neutralizing HIV-1 MPER Antibody DOI Creative Commons
Sara Insausti, Ander Ramos-Caballero, Brian Wiley

et al.

ACS Applied Materials & Interfaces, Journal Year: 2024, Volume and Issue: 16(44), P. 59934 - 59948

Published: Oct. 24, 2024

Establishment of interactions with the envelope lipids is a cardinal feature broadly neutralizing antibodies (bnAbs) that recognize Env membrane-proximal external region (MPER) HIV. The lipid constitutes relevant component full "quinary" MPER epitope, and thus may be optimized through engineering their capacity to interact lipids. However, role chemically complex nanoenvironment in mechanism molecular recognition viral neutralization remains poorly understood. To approach this issue, we computationally experimentally investigated antibody 10E8 versions engineered enhance epitope membrane affinity by grafting bulky aromatic compounds. Our data revealed correlation between potency establishment favorable small headgroup cholesterol phosphatidylethanolamine, evolving after specific engagement MPER. Molecular dynamics simulations modified Fabs an MPER-Transmembrane Domain helix supported generation causing localized deformation thick, rigid identified sphingomyelin preferentially occupying phospholipid-binding site 10E8. Together, these appear facilitate insertion epitope. These findings implicate individual molecules function bnAbs, validate targeted chemical modification as method optimize antibodies, suggest pathways for peptide-liposome vaccine development.

Language: Английский

Citations

1
Ab initio prediction of specific phospholipid complexes and membrane association of HIV-1 MPER antibodies by multi-scale simulations DOI Open Access
Colleen Maillie, Jay Golden, Ian A. Wilson

et al.

Published: Nov. 20, 2024

A potent class of HIV-1 broadly neutralizing antibodies (bnAbs) targets the envelope glycoprotein’s membrane proximal exposed region (MPER) through a proposed mechanism where hypervariable loops embed into lipid bilayers and engage headgroup moieties alongside epitope. We address feasibility determinant molecular features this using multi-scale modeling. All-atom simulations 4E10, PGZL1, 10E8 LN01 docked onto HIV-like membranes consistently form phospholipid complexes at key complementarity-determining loop sites, solidifying that stable specific interactions anchor bnAbs to surfaces. Ancillary protein-lipid contacts reveal surprising contributions from antibody framework regions. Coarse-grained effectively capture embedding membranes. Simulations estimating protein-membrane interaction strength for PGZL1 variants along an inferred maturation pathway show bilayer affinity is evolved correlates with neutralization potency. The modeling demonstrated here uncovers insights participation in antibodies’ recognition proteins highlights prioritize vaccine design.

Language: Английский

Citations

0
Ab initioprediction of specific phospholipid complexes and membrane association of HIV-1 MPER antibodies by multi-scale simulations DOI Creative Commons
Colleen Maillie, Jay Golden, Ian A. Wilson

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 5, 2023

Summary A potent class of HIV-1 broadly neutralizing antibodies (bnAbs) targets the envelope glycoprotein’s membrane proximal exposed region (MPER) through a proposed mechanism where hypervariable loops embed into lipid bilayers and engage headgroup moieties alongside epitope. We address feasibility determinant molecular features this using multi-scale modeling. All-atom simulations 4E10, PGZL1, 10E8 LN01 docked onto HIV-like membranes consistently form phospholipid complexes at key complementarity-determining loop sites, solidifying that stable specific interactions anchor bnAbs to surfaces. Ancillary protein-lipid contacts reveal surprising contributions from antibody framework regions. Coarse-grained effectively capture embedding membranes. Simulations estimating protein-membrane interaction strength for PGZL1 variants along an inferred maturation pathway show bilayer affinity is evolved correlates with neutralization potency. The modeling demonstrated here uncovers insights participation in antibodies’ recognition proteins highlights prioritize vaccine design.

Language: Английский

Citations

0
Ab initio prediction of specific phospholipid complexes and membrane association of HIV-1 MPER antibodies by multi-scale simulations DOI Open Access
Colleen Maillie, Jay Golden, Ian A. Wilson

et al.

Published: Aug. 25, 2023

A potent class of HIV-1 broadly neutralizing antibodies (bnAbs) targets the envelope glycoprotein's membrane proximal exposed region (MPER) through a proposed mechanism where hypervariable loops embed into lipid bilayers and engage headgroup moieties alongside epitope. We address feasibility determinant molecular features this using multi-scale modeling. All-atom simulations 4E10, PGZL1, 10E8, LN01 docked onto HIV-like membranes consistently form phospholipid complexes at key complementarity-determining loop sites, solidifying that stable specific interactions anchor bnAbs to surfaces. Ancillary protein-lipid contacts reveal surprising contributions from antibody framework regions. Coarse-grained effectively capture embedding membranes. Simulations estimating protein-membrane interaction strength for PGZL1 variants along an inferred maturation pathway show bilayer affinity is evolved correlates with neutralization potency. The modeling demonstrated here uncovers insights participation in antibodies' recognition proteins highlights prioritize vaccine design.

Language: Английский

Citations

0