02510nas a2200253 4500008004100000022001400041245012800055210007000183260000900253300001400262490000700276520160600283653002801889653002901917653001401946653003801960653004001998653002102038100002302059700001602082700001602098700001502114856012702129 2026 eng d a1948-719300aCombined effects of mutation and ionic strength onα-synuclein reveal generic features of aggregation-pronemonomeric states0 aCombined effects of mutation and ionic strength onαsynuclein rev cJUL  a2752-27700 v173 a

alpha-Synuclein (alpha S) is a highly charged, intrinsically disordered protein (IDP) whose aberrant aggregation is linked to Parkinson's disease (PD). Along with wild-type (WT) alpha S, five single-point mutants (A30P, E46K, H50Q, G51D, and A53T) are implicated in familial PD. To resolve contradictory experimental observations under varying solution conditions, we investigated how ionic strength modulates the relative aggregation propensity of these six monomeric alpha S variants using atomistic simulations. Structural and energetic analyses at global, domain, and residue levels revealed that aggregation propensity rankings switch with increasing ionic strength but stabilize beyond physiological concentration, while A53T and H50Q consistently remain highly aggregation-prone. We additionally identified electrostatic-driven decoupling between global and local motions. Aggregation-prone monomers preferentially populate semicompact ensembles with beta-sheet propensity, an exposed and stiff N-terminus with fewer interdomain contacts, a flexible yet compact C-terminus, and an NAC domain that is either under-protected and stiff or flexible and poorly hydrated. These monomers further exhibit strong intramolecular stabilization, poor solvation, counterion binding, and subdiffusive collapsing dynamics that may facilitate intermolecular encounters. We justified aggregation propensity trends across ionic strengths, validated physiological trends using a dimer model, suggested a generic monomer-to-aggregate mechanism, and reconciled simulations with experimental variability.

10aconformationallandscape10aelectrostatic modulation10aHydration10aintrinsically disordered proteins10amolecular flexibilityand compaction10apolymer dynamics1 aTammara, Vaishnavi1 aDas, Ankita1 aDesai, Zion1 aDas, Atanu uhttps://library.ncl.res.in/content/combined-effects-mutation-and-ionic-strength-on%CE%B1-synuclein-reveal-generic-features