Multistate and functional protein design using RoseTTAFold sequence space diffusion
Tuesday Dec 10th, 4-5pm EST | Jacob Gershon, PhD student, Sidney Lisanza, PhD and Sam Tipps, PhD student (UWashington & IPD)
Abstract: Protein denoising diffusion probabilistic models are used for the de novo generation of protein backbones but are limited in their ability to guide generation of proteins with sequence-specific attributes and functional properties. To overcome this limitation, we developed ProteinGenerator (PG), a sequence space diffusion model based on RoseTTAFold that simultaneously generates protein sequences and structures. Beginning from a noised sequence representation, PG generates sequence and structure pairs by iterative denoising, guided by desired sequence and structural protein attributes. We designed thermostable proteins with varying amino acid compositions and internal sequence repeats and cage bioactive peptides, such as melittin. By averaging sequence logits between diffusion trajectories with distinct structural constraints, we designed multistate parent–child protein triples in which the same sequence folds to different supersecondary structures when intact in the parent versus split into two child domains. PG design trajectories can be guided by experimental sequence–activity data, providing a general approach for integrated computational and experimental optimization of protein function.
Jacob is a PhD student at the Institute for Protein Design (University of Washington). His research focuses on developing deep generative models for protein design, with the ultimate goal of leveraging these tools to create innovative materials.
Sidney is a research scientist at Prescient Design and holds a PhD from the Institute for Protein Design (University of Washington). His primary research interest is in designing proteins that can modulate the immune system in precise and predefined ways.
Sam is a PhD student at the Institute for Protein Design (University of Washington). He is working on designing novel nanomaterials embedded with functional peptides to stimulate T cells effectively.