Quantifying biomolecular diffusion with a "spherical cow" model

TL;DR

This paper discusses simplified structure-based models, likened to a 'spherical cow', for understanding biomolecular diffusion and folding dynamics in high-dimensional energy landscapes, providing educational insights.

Contribution

It introduces a class of simplified, spherical cow-like models for exploring biomolecular diffusion and folding, with an educational tutorial for diverse audiences.

Findings

Models capture broad energetic landscape features

Facilitate understanding of folding pathways

Serve as educational tools for physics and biology

Abstract

The dynamics of biological polymers, including proteins, RNA, and DNA, occur in very high-dimensional spaces. Many naturally-occurring polymers can navigate a vast phase space and rapidly find their lowest free energy (folded) state. Thus, although the search process is stochastic, it is not completely random. Instead, it is best described in terms of diffusion along a downhill free energy landscape. In this context, there have been many efforts to use simplified representations of the energetics, for which the potential energy is chosen to be a relatively smooth function with a global minima that corresponds to the folded state. That is, instead of including every type of physical interaction, the broad characteristics of the landscape are encoded in approximate energy functions. We describe a particular class of models, called structure-based models, that can be used to explore the diffusive properties of biomolecular folding and conformational rearrangements. These energy functions may be regarded as the "spherical cow" for modeling molecular biophysics. We discuss the physical principles underlying these models and provide an entry-level tutorial, which may be adapted for use in curricula for physics and non-physics majors.