Biology subjects

Bililign, Y.

Publications and source records attributed to Bililign, Y..

3 recordsLinked to original sources

bioRxiv2026

Germline-somatic residue synergy reshapes antibody encounter state pathways to enhance HIV 1 recognition

Antibodies initiate antigen recognition through short-lived encounter states. These states are structurally distinct from the bound state and allow an antibody to reach the epitope from diverse approach angles. We previously showed that encounter states enable broadly neutralizing HIV-1 antibodies to access protected epitopes, but how these states evolve during affinity maturation is unknown. Here, we defined encounter-state ensembles for two intermediates in a glycan-dependent antibody clonal lineage using extensive molecular dynamics simulations and Markov state modeling. Somatic mutations in the more mature member did not stabilize the bound state. Instead, they created early glycan-mediated interactions that reoriented the antibody during approach and markedly increased the association rate. This reorientation redistributed productive encounter states across a larger antigen surface. This expanded the antigen surface area over which collisions led to productive binding. The modified encounter state landscape positioned germline residues for conserved contacts and provided a kinetic route that naturally bypasses steric barriers at the epitope. Together, these results show that affinity maturation can proceed by reshaping encounter pathways rather than altering the final complex, revealing a generalizable mechanism by which somatic-germline synergy enhances antigen recognition.

immunology↗

bioRxiv2023

Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies

Vaccine development targeting rapidly evolving pathogens such as HIV-1 requires induction of broadly neutralizing antibodies (bnAbs) with conserved paratopes and mutations, and, in some cases, the same Ig-heavy chains. The current trial-and-error search for immunogen modifications that improve selection for specific bnAb mutations is imprecise. To precisely engineer bnAb boosting immunogens, we used molecular dynamics simulations to examine encounter states that form when antibodies collide with the HIV-1 Envelope (Env). By mapping how bnAbs use encounter states to find their bound states, we identified Env mutations that were predicted to select for specific antibody mutations in two HIV-1 bnAb B cell lineages. The Env mutations encoded antibody affinity gains and selected for desired antibody mutations in vivo. These results demonstrate proof-of-concept that Env immunogens can be designed to directly select for specific antibody mutations at residue-level precision by vaccination, thus demonstrating the feasibility of sequential bnAb-inducing HIV-1 vaccine design.

immunology↗

bioRxiv2023

Microsecond dynamics control the HIV-1 envelope conformation

The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although significant progress has been made in understanding the structures of various Env conformations and transition intermediates that occur within the millisecond timescale, faster transitions in the microsecond timescale have not yet been observed. In this study, we employed time-resolved, temperature-jump small angle X- ray scattering to monitor structural rearrangements in an HIV-1 Env ectodomain construct with microsecond precision. We detected a transition correlated with Env opening that occurs in the hundreds of microseconds range and another more rapid transition that preceded this opening. Model fitting indicated that the early rapid transition involved an order-to-disorder transition in the trimer apex loop contacts, suggesting that conventional conformation-locking design strategies that target the allosteric machinery may be ineffective in preventing this movement. Utilizing this information, we engineered an envelope that locks the apex loop contacts to the adjacent protomer. This modification resulted in significant angle-of-approach shifts in the interaction of a neutralizing antibody. Our findings imply that blocking the intermediate state could be crucial for inducing antibodies with the appropriate bound state orientation through vaccination.

biophysics↗