Molecular Dynamics Ensemble Refinement of Intrinsically Disordered Peptides According to Deconvoluted Spectra from Circular Dichroism.

Biophysical Journal
Jacob C EzerskiMargaret S Cheung

Abstract

We have developed a computational method of atomistically refining the structural ensemble of intrinsically disordered peptides (IDPs) facilitated by experimental measurements using circular dichroism spectroscopy (CD). A major challenge surrounding this approach stems from the deconvolution of experimental CD spectra into secondary structure features of the IDP ensemble. Currently available algorithms for CD deconvolution were designed to analyze the spectra of proteins with stable secondary structures. Herein, our work aims to minimize any bias from the peptide deconvolution analysis by implementing a non-negative linear least-squares fitting algorithm in conjunction with a CD reference data set that contains soluble and denatured proteins (SDP48). The non-negative linear least-squares method yields the best results for deconvolution of proteins with higher disordered content than currently available methods, according to a validation analysis of a set of protein spectra with Protein Data Bank entries. We subsequently used this analysis to deconvolute our experimental CD data to refine our computational model of the peptide secondary structure ensemble produced by all-atom molecular dynamics simulations with implicit solvent....Continue Reading

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Methods Mentioned

BETA
circular dichroism
electron microscopy
NMR
Protein Circular Dichroism
X-ray

Software Mentioned

BeStSeL
CPPTRAJ
DSSP
SELCON3
CDPro
AMBER
AMBERTOOLS
CATS
CIDER
IDP

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