Biophysical Walks on Fitness Landscapes

Fitness landscape (FL) is a common metaphoric description of genotype-phenotype relationship (GPR). However its precise nature is not known: ‘’Axes” on the pictorial presentations of FL remain unlabeled. In this talk I will present our theoretical and experimental efforts, to outline FL of viruses and bacteria in terms of biophysical properties of their proteins such as thermodynamic stability, catalytic activity and intracellular abundances as well as functional and non-functional interactions with other proteins. We develop computational multiscale models where link between effect of mutations on molecular properties of proteins and fitness is derived from experiments where rational genetic variation is introduced in ORFs of essential genes dihydrofolate reductase and adenylate kinase. The molecular fingerprints of mutated proteins are then mapped to fitness of strains where mutations are introduced on the chromosome using genomic editing technique. We show how genetic variation introduces major fitness barriers that can be overcome in evolutionary dynamics. Metabolomic, genomic and proteomic comparative analyses of ‘’naïve’’ genomically edited and evolved strains highlights major elements in the relationship between molecular and organismal traits providing a crucial feedback for computational modeling.