CNRS - AIX MARSEILLE UNIV : UMR7257

Accueil du site > Communication > Séminaires > Lundi 14 mai à 11h : Sarel Fleishman, Weizmann Institute of Science, Dept. (...)

Lundi 14 mai à 11h : Sarel Fleishman, Weizmann Institute of Science, Dept. Biomolecular Sciences, Rehovot, Israël (amphi CIML). "Computational design of antibodies, enzymes and vaccine immunogens"

Abstract (...)

Abstract Computational​ ​protein​ ​design​ ​is​ ​making​ ​substantial​ ​progress,​ ​and​ ​has​ ​generated​ ​stable​ ​and accurate​ ​small​ ​protein​ ​folds,​ ​coiled​ ​coils,​ ​and​ ​large​ ​oligomeric​ ​assemblies.​ ​The​ ​design​ ​of​ ​protein binders​ ​and​ ​enzymes,​ ​by​ ​contrast,​ ​has​ ​been​ ​less​ ​successful,​ ​mainly​ ​due​ ​to​ ​the​ ​large​ ​size​ ​and complexity​ ​of​ ​most​ ​functional​ ​proteins.​ ​To​ ​address​ ​the​ ​challenge​ ​of​ ​designing​ ​functional​ ​proteins, we​ ​have​ ​developed​ ​a​ ​strategy​ ​that​ ​uses​ ​evolutionary​ ​principles​ ​to​ ​guide​ ​atomistic​ ​design calculations​ ​in​ ​the​ ​Rosetta​ ​software​ ​suite​ ​for​ ​biomolecular​ ​design.​ ​Using​ ​this​ ​strategy,​ ​we developed​ ​the​ ​PROSS​ ​algorithm​ ​and​ ​webserver​ ​for​ ​fully​ ​automated​ ​protein​ ​stability​ ​design ;​ ​for instance,​ ​we​ ​designed​ ​the​ ​first​ ​variants​ ​of​ ​the​ ​human​ ​enzyme​ ​acetylcholinesterase​ ​that​ ​are expressible,​ ​stable​ ​and​ ​fully​ ​functional​ ​in​ ​bacterial​ ​cells.​ ​We​ ​extended​ ​the​ ​method​ ​to​ ​the​ ​design​ ​of challenging​ ​microbial​ ​proteins​ ​that​ ​may​ ​serve​ ​as​ ​vaccine​ ​immunogens,​ ​and​ ​applied​ ​it​ ​to​ ​designing a​ ​variant​ ​of​ ​the​ ​malaria​ ​parasite​ ​protein​ ​RH5​ ​that​ ​can​ ​be​ ​produced​ ​economically​ ​in​ ​bacterial​ ​cells and​ ​is​ ​stable​ ​in​ ​the​ ​elevated​ ​temperatures​ ​typical​ ​of​ ​sub-Saharan​ ​Africa,​ ​where​ ​malaria​ ​is prevalent.​ ​This​ ​strategy​ ​can​ ​also​ ​be​ ​used​ ​to​ ​design​ ​variants​ ​of​ ​antibodies​ ​and​ ​enzymes​ ​with 100-1,000​ ​fold​ ​improved​ ​affinity​ ​or​ ​catalytic​ ​rate.​ ​We​ ​also​ ​extended​ ​this​ ​strategy​ ​to​ ​designing​ ​new antibodies​ ​and​ ​enzymes​ ​based​ ​on​ ​backbone​ ​conformations​ ​and​ ​sequence-conservation​ ​data​ ​from natural​ ​ones.​ ​This​ ​method,​ ​called​ ​AbDesign,​ ​has​ ​generated​ ​new​ ​binders​ ​and​ ​enzymes​ ​with​ ​high stability,​ ​specificity,​ ​activity,​ ​and​ ​accuracy.​ ​The​ ​design​ ​methods​ ​are​ ​fully​ ​automated,​ ​and​ ​will enable​ ​the​ ​complete​ ​computational​ ​design​ ​of​ ​antibodies​ ​or​ ​enzymes​ ​with​ ​desired​ ​molecular properties.
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