title: A "fuzzy"-logic language for encoding multiple physical traits in biomolecules.
abstract: To carry out their activities, biological macromolecules balance different physical traits, such as stability, interaction affinity, and selectivity. How such often opposing traits are encoded in a macromolecular system is critical to our understanding of evolutionary processes and ability to design new molecules with desired functions. We present a framework for constraining design simulations to balance different physical characteristics. Each trait is represented by the equilibrium fractional occupancy of the desired state relative to its alternatives, ranging from none to full occupancy, and the different traits are combined using Boolean operators to effect a "fuzzy"-logic language for encoding any combination of traits. In another paper, we presented a new combinatorial backbone design algorithm AbDesign where the fuzzy-logic framework was used to optimize protein backbones and sequences for both stability and binding affinity in antibody-design simulation. We now extend this framework and find that fuzzy-logic design simulations reproduce sequence and structure design principles seen in nature to underlie exquisite specificity on the one hand and multispecificity on the other hand. The fuzzy-logic language is broadly applicable and could help define the space of tolerated and beneficial mutations in natural biomolecular systems and design artificial molecules that encode complex characteristics.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Warszawski
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ravit
authors.initials: R
authors.lastname: Netzer
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Dan S
authors.initials: DS
authors.lastname: Tawfik
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: sarel@weizmann.ac.il.
authors.forename: Sarel J
authors.initials: SJ
authors.lastname: Fleishman
mesh_terms: D000465:Algorithms; D055592:Biophysical Phenomena; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D017143:Fuzzy Logic; D008958:Models, Molecular; D009154:Mutation; D015202:Protein Engineering / Q000379:methods; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D011506:Proteins
keywords: Rosetta; diminishing returns; multistate design; sequence optimization; stability-activity tradeoff