Computational design of closely related proteins that adopt two well-defined but structurally divergent folds

Abstract

The plasticity of naturally occurring protein structures, which can change shape considerably in response to changes in environmental conditions, is critical to biological function. While computational methods have been used for de novo design of proteins that fold to a single state with a deep free-energy minimum [P.-S. Huang, S. E. Boyken, D. Baker, Nature 537, 320-327 (2016)], and to reengineer natural proteins to alter their dynamics [], the de novo design of closely related sequences which adopt welldefined but structurally divergent structures remains an outstanding challenge. We designed closely related sequences (over 94% identity) that can adopt two very different homotrimeric helical bundle conformations-one short (∼66 Å height) and the other long (∼100 Å height)-reminiscent of the conformational transition of viral fusion proteins. Crystallographic and NMR spectroscopic characterization shows that both the short-and long-state sequences fold as designed. We sought to design bistable sequences for which both states are accessible, and obtained a single designed protein sequence that populates either the short state or the long state depending on the measurement conditions. The design of sequences which are poised to adopt two very different conformations sets the stage for creating large-scale conformational switches between structurally divergent forms.protein engineering | computational protein design | conformation change | calcium induced | protein switch

Ig-VAE: Generative Modeling of Protein Structure by Direct 3D Coordinate Generation

“…Over the past two decades, the field of protein design has made steady progress, with new computational methods providing novel solutions to challenging problems such as enzyme catalysis, viral inhibition, de novo structure generation and more [1,2,3,4,5,6,7,8,9]. Building on the improvements in force field accuracy and conceptual advancements in understanding structural engineering principles, computational protein design is seemingly ready to take on any engineering challenge.…”

Protein conformations à la carte, a step further in de novo protein design

“…This way of thinking has inspired scientists to not be satisfied with revealing fundamental principles but to apply them to create novel proteins with desired properties. The work of Wei et al (2) in PNAS is a relevant example of such efforts to demonstrate understanding of biophysical principles of protein structure and dynamics by designing a protein that can change its shape under specific solution conditions.…”

“…De novo protein design is different from the advances described before because it aims to explore a space that has not been previously visited in the evolutionary process but whose fundamental physical and chemical principles are maintained. The work of Wei et al (2) belongs to this effort to create desired properties from the exploration of first principles. In their research, they build from an extensive framework for protein modeling and design spearheaded by contributions of the Baker laboratory and members of the Institute for Protein Design at the University of Washington (12,14,15).…”

“…In a past study, the group created a de novo six-helix bundle, that is, a protein complex consisting of identical alpha helices that interact to form structures analogous to elongated rose bundles (14). Wei et al (2) aim to solve the problem of creating a protein that could be energetically stable in more than one conformation. Although substantial conformational changes upon mutation via protein engineering have been achieved in the past, notably an IgG-binding protein with a 4β + α fold transformed into an albumin-binding, 3-α fold (16), the work of Wei et al (2) pushes the boundaries of de novo design by building on top of a synthetic protein.…”

“…1C). Wei et al (2) found that, by creating mixtures of such layers, they could promote the presence of one state versus the other. For instance, more A layers favored the long state, and glycines in the hinge reduced favorable contributions to the long-state free energy.…”