Engineering and Design of Programmable Genome Editors

Programmable genome editors are enzymes that can be targeted to a specific location in the genome for making site-specific alterations or deletions. The engineering, design, and development of sequence-specific editors has resulted in a dramatic increase in the precision of editing for nucleotide sequences. These editors can target specific locations in a genome, in vivo. The genome editors are being deployed for the development of genetically modified organisms for agriculture and industry, and for gene therapy of inherited human genetic disorders, cancer, and immunotherapy. Experimental and computational studies of structure, binding, activity, dynamics, and folding, reviewed here, have provided valuable insights that have the potential for increasing the functional efficiency of these gene/genome editors. Biochemical and biophysical studies of the specificities of natural and engineered genome editors reveal that increased binding affinity can be detrimental because of the increase of off-target effects and that the engineering and design of genome editors with higher specificity may require modulation and control of the conformational dynamics.