title: An accurate binding interaction model in de novo computational protein design of interactions: if you build it, they will bind.
abstract: Computational protein design efforts aim to create novel proteins and functions in an automated manner and, in the process, these efforts shed light on the factors shaping natural proteins. The focus of these efforts has progressed from the interior of proteins to their surface and the design of functions, such as binding or catalysis. Here we examine progress in the development of robust methods for the computational design of non-natural interactions between proteins and molecular targets such as other proteins or small molecules. This problem is referred to as the de novo computational design of interactions. Recent successful efforts in de novo enzyme design and the de novo design of protein-protein interactions open a path towards solving this problem. We examine the common themes in these efforts, and review recent studies aimed at understanding the nature of successes and failures in the de novo computational design of interactions. While several approaches culminated in success, the use of a well-defined structural model for a specific binding interaction in particular has emerged as a key strategy for a successful design, and is therefore reviewed with special consideration.
authors.affiliation: Rosetta Design Group LLC, Fairfax, VA 22030, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA. Electronic address: nir.london@ucsf.edu.
authors.forename: Nir
authors.initials: N
authors.lastname: London
authors.affiliation: Rosetta Design Group LLC, Fairfax, VA 22030, USA. Electronic address: xavier@rosettadesigngroup.com.
authors.forename: Xavier
authors.initials: X
authors.lastname: Ambroggio
mesh_terms: D019943:Amino Acid Substitution; D003198:Computer Simulation; D019020:Directed Molecular Evolution; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D015202:Protein Engineering; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D012984:Software
chemical_list: D011506:Proteins
keywords: Binding interaction model; Computational design; De novo design; Enzyme design; Protein–protein interaction design; ROSETTA