title: Lessons in Protein Design from Combined Evolution and Conformational Dynamics.
abstract: Protein-protein interactions play important roles in the control of every cellular process. How natural selection has optimized protein design to produce molecules capable of binding to many partner proteins is a fascinating problem but not well understood. Here, we performed a combinatorial analysis of protein sequence evolution and conformational dynamics to study how calmodulin (CaM), which plays essential roles in calcium signaling pathways, has adapted to bind to a large number of partner proteins. We discovered that amino acid residues in CaM can be partitioned into unique classes according to their degree of evolutionary conservation and local stability. Holistically, categorization of CaM residues into these classes reveals enriched physico-chemical interactions required for binding to diverse targets, balanced against the need to maintain the folding and structural modularity of CaM to achieve its overall function. The sequence-structure-function relationship of CaM provides a concrete example of the general principle of protein design. We have demonstrated the synergy between the fields of molecular evolution and protein biophysics and created a generalizable framework broadly applicable to the study of protein-protein interactions.
authors.affiliation: Department of Physics, University of Houston, Houston, TX.|Center for Theoretical Biological Physics, Rice University, Houston, TX.
authors.forename: Swarnendu
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Department of Neurobiology and Anatomy, University of Texas, Health Science Center, Houston, TX.
authors.forename: M Neal
authors.initials: MN
authors.lastname: Waxham
authors.affiliation: Department of Physics, University of Houston, Houston, TX.|Center for Theoretical Biological Physics, Rice University, Houston, TX.
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Cheung
authors.affiliation: Department of Neurobiology and Anatomy, University of Texas, Health Science Center, Houston, TX.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D020013:Calcium Signaling; D002147:Calmodulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D019684:Magnoliopsida / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D002147:Calmodulin