A Charge-Encoded Rheostat Permits Helix Nucleation but Limits Propagation in Skp1

1 Conformational Flexibility Enables the Function of a BECN1 Region 2 Essential for Starvation-Mediated Autophagy

Switching Functional DNA-Binding Modes by Tuning Protein Order-Disorder Equilibria

A conserved sequence-ensemble-dynamics code in Nhp6A is revealed wherein not just stability, but also phosphorylation-induced conformational switching, disordered tail dynamics, and DNA binding-bending closely coordinate chromatin accessibility is revealed.

Structure, Diffusion, and Relaxation in a Charge-Neutral ProTalpha-Histone H1 Condensate

Condensates formed by oppositely charged intrinsically disordered proteins provide model systems for understanding how transient electrostatic interactions govern structure and dynamics in biomolecular assemblies. Here we investigate a nearly charge-neutral condensate composed of 50 Prothymosin alpha (ProTalpha) and 40 Histone H1 molecules using a single-bead-per-residue coarse-grained model combining the HPS hydropathy model for disordered regions with a Go model for the globular domain of Histone H1 under NPT conditions at pressures from 2 to 12 bar. We find that chain dimensions, including the radius of gyration (Rg), end-to-end distance (Ree), and their ratio R, are insensitive to pressure, indicating that chain conformations remain largely unchanged over the pressure range studied. Histone H1 exhibits systematically larger values of R than ProTalpha because of its globular-core plus disordered-tail architecture. Translational diffusion coefficients decrease monotonically with pressure, from approximately 0.22 to 0.06 nm^2/ns, with substantial chain-to-chain heterogeneity comparable to the mean diffusion coefficient. Chain relaxation follows a stretched exponential with beta less than 1 that decreases with pressure. ProTalpha relaxation times of approximately 12 to 40 ns obey Rouse scaling, whereas Histone H1 deviates because of the internal constraint imposed by its globular domain. ProTalpha-Histone H1 contact lifetimes of approximately 0.43 to 0.56 ns are much shorter than the Rouse relaxation time, placing the system firmly in the fast-exchange regime where transient electrostatic contacts renormalize chain friction rather than acting as permanent cross-links, consistent with the moderate stretching exponent beta of approximately 0.55 to 0.70 observed across all pressures.

The Gordian Knot Enhances Ubiquitin Binding in UCH-L1

Ser715 Phosphorylation Induces β-Hairpin Unfolding and Destabilization of FOXM1 Autoinhibition

FOXM1 is a cell proliferation-driving transcription factor activated by phosphorylation-induced conformational changes. In its inactive state, an intramolecular β-hairpin within the transactivation domain (TAD) binds the N-terminal repressor domain (NRD), forming a composite β-sheet that locks the protein in an autoinhibited conformation. Despite the known importance of this regulatory switch, the molecular events that unlock FOXM1 remain poorly characterized. Here, we performed 5 μs all-atom molecular dynamics simulations of human FOXM1b NRD-TAD complexes in both unphosphorylated and tetra-phosphorylated states, modeling four experimentally validated regulatory phosphosites. Our results showed that phosphorylation induces local unfolding of the β-hairpin beginning at Ser715, located at the hairpin turn, and propagates to global disruption of the NRD interface through hydrogen bond loss, salt bridge rupture, and secondary structure collapse. In contrast, the unphosphorylated complex maintains stable hairpin geometry and interdomain contacts. Additional replicate tetra-phosphorylated simulations and a monophosphorylated Ser715 simulation reproduced the β-hairpin unfolding event, supporting both reproducibility and the sufficiency of Ser715 phosphorylation in initiating this transition. Per-residue MM-PBSA energy decomposition further reveals that phosphorylation redistributes interdomain interaction energetics, with Ser715 emerging as the dominant locus of energetic perturbation despite the presence of multiple phosphosites. Together, these findings support a phosphorylation-triggered order-to-disorder transition that relieves FOXM1 autoinhibition and highlight Ser715 as a key structural and energetic switch. Our study provides a dynamic molecular framework for targeting FOXM1 activation via its regulatory fold.

Biomolecular Condensates Dictate the Folding Landscape of Protein Alpha-Helices.

This work investigates how protein folding landscapes are altered inside condensates, using the protein α-helix as a model folded domain and develops a chemically specific, residue-resolution model for quantification of α-helical folding and applies it to characterize diverse helices within condensates of varying physicochemical properties.