Staphylococcal enterotoxin B (SEB) simultaneously crosslinks MHC class II antigen and TCR, promoting proliferation of T cells and releasing a large number of toxic cytokines. In this report, we computationally examined the possibility of using a single-chain biparatopic bispecific antibody to target SEB and prevent TCR binding. The design was inspired by the observation that mixing two anti-SEB antibodies 14G8 and 6D3 can block SEB-TCR activation, and we used 14G8-6D3-SEB tertiary crystal structure as a template. Twelve simulation systems were constructed to systematically examine the effects of the designed bispecific scFV MB102a, including isolated SEB, MB102a with different linkers, MB102a-SEB complex, MB102a-SEB-TCRβ complex, MB102a-SEB-TCR-MHC II complex, and MB102a-SEB-MHC II. Our all atom molecular dynamics simulations (total 18,900 ns) confirmed that the designed single-chain bispecific antibody may allosterically prevent SEB-TCRβ chain binding and inhibit SEB-TCR-MHC II formation. Subsequent analysis indicated that the binding of scFV to SEB correlates with SEB-TCR binding site motion and weakens SEB-TCR interactions.
Cobalamin riboswitch is a cis-regulatory
element widely found in
the 5′-UTRs of the vitamin B12-associated genes in bacteria,
resulting in modulation and production of a particular protein. Thermoanaerobacter
tengcongensis (Tte) AdoCbl riboswitches are the largest
of the known riboswitches with 210 nucleotides, partially due to its
long peripheral P6-extension, which enable high affinity of AdoCbl.
Two structural elements, T-loop/T-looplike motif and kissing loop
are key to the global folding of the RNA. While the structure of the TteAdoCbl riboswitch complex is known, we still do not understand
the structure and conformation before AdoCbl ligand recognition. In
order to delineate the conformational changes and the stabilities
of long-range interactions, we have performed extensive all-atom replica-exchange
molecular dynamics simulations of the TteAdoCbl riboswitch
with a total simulation time of 2296 ns. We found that both the T-loop/T-looplike
motif and kissing loop are very stable with ligand binding. The gating
conformation changes of P6-extension allow the ligand to bind to the
preorganized kissing loop binding pocket. The T-loop/T-looplike motif
has much more hydrogen bonds than observed in TteAdoCbl riboswitch complex crystal structure, indicating an allosteric
response of the T-loop/T-looplike motif. Our study demonstrated that
the conformational ensemble of TteAdoCbl riboswitch
provides stable structural elements for conformation selection and
population shift in cobalamin recognition.
Recent progress in epitope prediction has shown promising results in the development of vaccines and therapeutics against various diseases. However, the overall accuracy and success rate need to be improved greatly to gain practical application significance, especially conformational epitope prediction. In this review, we examined the general features of antibody–antigen recognition, highlighting the conformation selection mechanism in flexible antibody–antigen binding. We recently highlighted the success and warning signs of antibody epitope predictions, including linear and conformation epitope predictions. While deep learning-based models gradually outperform traditional feature-based machine learning, sequence and structure features still provide insight into antibody–antigen recognition problems.
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