title: Protein engineering and the use of molecular modeling and simulation: the case of heterodimeric Fc engineering.
abstract: Computational and structure guided methods can make significant contributions to the development of solutions for difficult protein engineering problems, including the optimization of next generation of engineered antibodies. In this paper, we describe a contemporary industrial antibody engineering program, based on hypothesis-driven in silico protein optimization method. The foundational concepts and methods of computational protein engineering are discussed, and an example of a computational modeling and structure-guided protein engineering workflow is provided for the design of best-in-class heterodimeric Fc with high purity and favorable biophysical properties. We present the engineering rationale as well as structural and functional characterization data on these engineered designs.
authors.affiliation: Zymeworks Inc., 540-1385 West 8th Avenue, Vancouver, British Columbia V6H 3V9, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Spreter Von Kreudenstein
authors.affiliation: Zymeworks Inc., 540-1385 West 8th Avenue, Vancouver, British Columbia V6H 3V9, Canada.
authors.forename: Paula I
authors.initials: PI
authors.lastname: Lario
authors.affiliation: Zymeworks Inc., 540-1385 West 8th Avenue, Vancouver, British Columbia V6H 3V9, Canada. Electronic address: sdixit@zymeworks.com.
authors.forename: Surjit B
authors.initials: SB
authors.lastname: Dixit
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000918:Antibody Specificity; D001665:Binding Sites; D006801:Humans; D006860:Hydrogen Bonding; D007141:Immunoglobulin Fc Fragments / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D056004:Molecular Dynamics Simulation; D015202:Protein Engineering; D055550:Protein Stability; D017433:Protein Structure, Secondary
chemical_list: D007141:Immunoglobulin Fc Fragments
keywords: Antibody engineering; Bispecific antibody; CCSD; CI; Computational protein engineering; Fc engineering; Heterodimeric antibody; Hphobic; KBP; KiH; LJ; Lennard-Jones contributions; MD; RDF; RMSD; RMSF; SASA; Tm; charge inversion; close contact surface density (Δσ(tot)); elec; electrostatic contributions; h-bond; hydrogen bond; hydrophobic; knob in hole; knowledge based potential; molecular dynamics; radial distribution function; root mean squared deviation; root mean squared fluctuation; solvent exposed surface area; thermal melting temperature; van der Waals interaction; vdW