Pathogenic Variation & Environmental Stress

How does a sequence change become a molecular phenotype?

Genetic studies can associate a variant with disease without explaining what it does to the encoded protein. We investigate that missing mechanistic step. A substitution can change the conformations a protein samples, redirect communication between distant regions or alter its interactions with binding partners. Those effects may be missed by comparing static structures alone.

We connect sequence variation to molecular behavior through computational structural biology and collaborations that provide experimental tests. Our emphasis is on interpretable mechanisms: which interactions change, how collective motion responds and what those changes imply for the biological function of the molecule.

PR65 demonstrates why dynamics matters

The PR65 scaffold study provides a published example of this approach. We identified mechanically important hinge sites, examined selected substitutions with atomistic simulations and compared their behavior with single-molecule measurements. Some substitutions favored more extended conformations, while another produced the opposite tendency. The agreement between computational and experimental results shows how a sequence change can reshape conformational adaptability.

The key outcome is a physical explanation rather than a pathogenicity label alone. The experiments and simulations relate a variant to a change in the scaffold’s behavior, providing a basis for examining how such changes could influence the assembly and regulation of PP2A.

Connecting a sequence change to molecular behavior. The published PR65 study combines computational selection and simulation of hinge-site variants with protein characterization and single-molecule measurements. Reproduced unchanged from Banerjee et al. (2024), Figure 1. The diagram describes completed work in that study. Banerjee et al. (2024)

Recognition depends on sequence and molecular context

Our HLA-B*51 research examines a complementary problem: how an antigen-presenting molecule associated with inflammatory disease recognizes different peptide sequences. The 2026 study identified a common interaction pattern modified by peptide length. Together with the PR65 work, it illustrates how sequence-dependent effects become understandable when analyzed through the motions and interactions of an entire molecular complex.

Molecular context also includes binding partners and ligands. Our PP2A studies show that a ligand’s binding arrangement and its effect on scaffold dynamics depend on whether PR65 is considered alone or within an assembly. This motivates interpreting a variant within the states and interactions relevant to function.

Global hinge sites organize collective PR65 motions. Predicted displacement profiles and structural views identify residues that help coordinate deformation of the scaffold. Reproduced unchanged from Banerjee et al. (2024), Figure 3. Banerjee et al. (2024)

Environmental stress as a research direction

We are extending this mechanistic perspective to disease-associated proteins under environmental stress. A project selected by NASA Space Biology in September 2026 investigates pathogenic mutations under conditions relevant to spaceflight. At the broad scientific level, the question is how environmental context changes the molecular consequences of a genetic variant. This is a current research direction, not a completed finding.

The broader aim is to understand when context amplifies, reduces or changes the effects of a sequence variant. Linking genetic information to molecular behavior can help formulate better mechanistic hypotheses for disease research on Earth as well as in space-related biology.

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