Efficient enumeration and visualization of helix-coil ensembles

• Published in: Biophysical journal Vol. 123; no. 3; pp. 317 - 333
• Main Authors: Hughes, Roy G., Zhao, Shiwen, Oas, Terrence G., Schmidler, Scott C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.02.2024
• Subjects: Circular Dichroism; Peptides - chemistry
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/j.bpj.2023.12.021

Helix-coil models are routinely used to interpret circular dichroism data of helical peptides or predict the helicity of naturally-occurring and designed polypeptides. However, a helix-coil model contains significantly more information than mean helicity alone, as it defines the entire ensemble—the equilibrium population of every possible helix-coil configuration—for a given sequence. Many desirable quantities of this ensemble are either not obtained as ensemble averages or are not available using standard helicity-averaging calculations. Enumeration of the entire ensemble can allow calculation of a wider set of ensemble properties, but the exponential size of the configuration space typically renders this intractable. We present an algorithm that efficiently approximates the helix-coil ensemble to arbitrary accuracy by sequentially generating a list of the M highest populated configurations in descending order of population. Truncating this list of (configuration, population) pairs at a desired accuracy provides an approximating sub-ensemble. We demonstrate several uses of this approach for providing insight into helix-coil ensembles and folding mechanisms, including landscape visualization.