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Computational design with flexible backbone sampling for protein remodeling and scaffolding of complex binding sites
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Resumo(s)
Computational protein design has achieved several milestones, including the design of a
new protein fold, the design of enzymes for reactions that lack natural catalysts, and the
re-engineering of protein-protein and protein-DNA binding speci city. These achievements
have spurred demand to apply protein design methods to a wider array of research problems.
However, the existing computational methods have largely relied on xed-backbone
approaches that may limit the scope of problems that can be tackled. Here, we describe four
computational protocols - side chain grafting,
exible backbone remodeling, backbone grafting,
and de novo sca old design - that expand the methodological protein design repertoire,
three of which incorporate backbone
exibility. Brie
y, in the side chain grafting method,
side chains of a structural motif are transplanted to a protein with a similar backbone conformation;
in
exible backbone remodeling, de novo segments of backbone are built and
designed; in backbone grafting, structural motifs are explicitly grafted onto other proteins;
and in de novo sca olding, a protein is folded and designed around a structural motif.
We developed these new methods for the design of epitope-sca old vaccines in which viral
neutralization epitopes of known three-dimensional structure were transplanted onto nonviral
sca old proteins for conformational stabilization and immune presentation.(...)
Descrição
Dissertation presented to obtain the Doutoramento (Ph.D.) degree in Biochemistry at the
Instituto de Tecnologia Qu mica e Biol ogica da Universidade Nova de Lisboa
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Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica