Molecular dynamics simulations of intrinsically disordered protein regions enable biophysical interpretation of variant effect predictors.

Predictive models for missense variant pathogenicity offer little functional interpretation for intrinsically disordered regions, since they rely on conservation and coevolution across homologous sequences. To understand the extent to which biophysics modulates model performance compared to genomic conservation, we model biophysics of IDRs explicitly for improved interpretation of variant effects. We develop MDmis, a method that uses biophysical features extracted from molecular dynamics (MD) simulations of IDRs to predict pathogenicity. We find that pathogenic variants in Long IDRs manifest differently, with transient order and depleted solvent access, compared to those in Short IDRs. Using MD simulations of sequences with single missense variants, we identify stronger evidence for pathogenic effects in Long IDRs compared to Short IDRs. MDmis, when combined with conservation information, achieves strong predictive accuracy of pathogenicity of variants in Long IDRs. Overall, extracting information from MD simulations can help understand the drivers of predictive performance and elucidate biophysical behaviors affected by pathogenic variants.