Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of folded proteins play significant roles in cell signaling, regulation and recognition. While IDPs and IDRs are involved in many neurodegenerative diseases as well as cancer, they are commonly considered “undruggable” due to the lack of inherent structures that can serve as a target for drug-binding. To overcome this challenge, we explore the feasibility of drug-development protocols based on binding-induced folding mechanisms. Specifically, we plan to identify target sequences within IDPs/IDRs that are susceptible to folding into alpha-helical structures with a minimal free energy cost. We will then develop ligands that bind specifically to the resulting alpha-helix with a negative binding free energy that compensates for the free energy cost of folding the targeted IDP/IDR sequence. Quantitative predictions of free energy cost associated with the formation of alpha-helical structures for selected target sequences are the logical first step in this process and are expected to require a higher level of detail than empirical predictions based on average helix propensities.<br/>We use atomistic molecular dynamics simulations of peptides coupled with Umbrella sampling to generate free energy profiles that describe the transition of peptide conformations from intrinsically disordered ensembles into alpha-helical structures. As a collective coordinate to describe folding, we employ a differentiable function of the coordinates that correlates with the number of intramolecular hydrogen bonds stabilizing the alpha-helical state (Camilloni <i>et al</i>., Proteins (2008), 71, 1647–1654).<br/>The first target considered in this project is the IDR of the c-Myc protein, which is an important transcription factor and is overexpressed in tumor cells associated with breast, colon, gynecological and hepatocellular cancer. In addition to selected IDP/IDR target sequences, we study poly-alanine as a reference for an alpha-helical peptide, which reveals significant differences between distinct classes of state-of-the-art empirical force fields commonly used for protein simulations.

Free energy cost for binding-induced folding of intrinsically disordered peptides

ACS Spring 2022

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