Cancer Biology & Therapeutic Targets

How can molecular dynamics explain therapeutic response?

A protein’s response to a mutation or a drug depends on the conformations it can adopt and the interactions it forms with other molecules. We investigate these relationships in proteins involved in cancer-related signaling. Our objective is to explain how a perturbation changes molecular behavior and whether that change supports or disrupts a functional assembly.

Protein phosphatase 2A, or PP2A, provides a central example. Its scaffold subunit PR65 brings together catalytic and regulatory subunits. PR65 must be stable enough to maintain this assembly and flexible enough to support its changing interactions. This combination makes scaffold dynamics an essential part of understanding PP2A regulation.

The PR65 scaffold in the PP2A complex and in an extended conformation. The catalytic and regulatory subunits assemble against its curved HEAT-repeat architecture. Reproduced unchanged from Yilmaz et al. (2026), Figure 1. The figure distinguishes experimentally resolved starting structures from the dynamics subsequently examined by simulation. Yilmaz et al. (2026)

Mutations alter conformational adaptability

Our 2024 collaborative study combined computational identification of PR65 hinge sites, atomistic simulations, protein characterization and nanoaperture optical tweezers. Selected substitutions shifted the scaffold’s conformational preferences in ways that were consistent between simulations and single-molecule measurements. The results demonstrate that a mutation can change a protein’s mechanical behavior without simply destroying its folded structure.

This distinction matters for variant interpretation. A sequence change may alter the balance between compact and extended conformations, affecting interactions with partner subunits. Our work therefore evaluates conformational ensembles and collective motion alongside conventional structural and stability measures.

Small molecules remodel the PR65 scaffold

Our 2026 molecular dynamics study examined how small-molecule PP2A activators bind to PR65 and influence its dynamics. The simulations identified differences between binding to the isolated scaffold and binding in the assembled complex, and supported a mechanism in which ligand binding favors conformations compatible with subsequent assembly. The work explains why the molecular context of a binding site matters when interpreting a static structure.

A complementary 2026 collaboration combined optical tweezers, ensemble measurements and computational analysis to compare the effects of different ligands. ATUX-8385 stabilized PR65 across its repeat structure and reduced misfolding in the mechanical experiments, while the nonfunctional comparator produced a different response. Simulations connected these effects to distinct binding arrangements and conformational behavior. These studies investigate a molecular mechanism; they do not establish clinical benefit.

A proposed mechanism connecting small-molecule binding, PR65 opening and PP2A assembly. This is the mechanistic model presented in the source paper, rather than a direct movie of assembly or a demonstrated treatment response. Reproduced unchanged from Naqvi et al. (2026), Figure 8. Naqvi et al. (2026)

From binding to functional control

Our single-molecule PR65 binding collaboration and the broader analysis of global hinge sites reinforce a common point: where a compound binds is only part of its mechanism. Its effects on protein motion, stability and partner interactions determine what follows. We use this perspective to connect ligand recognition with the assembly and regulation of molecular systems.

Our continuing direction is physics-informed therapeutic modulation, including allosteric small molecules and other molecular binders. We seek mechanistic explanations that connect the initial interaction to the desired functional state, with computational predictions interpreted alongside experimental evidence.

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