AllohubPy: Detecting Allosteric Signals Through An Information-theoretic Approach.

Abstract

Allosteric regulation is crucial for biological processes like signal transduction, transcriptional regulation, and metabolism, yet the mechanisms and macromolecular properties that govern it are still not well understood. Several methods have been developed over the years to study allosterism through different angles. Among the possible ways to study allosterism, information-theoretic approaches, like AlloHubMat or GSAtools, can be particularly effective due to their use of robust statistics and the possibility to be combined with graph analysis. These methods capture local conformational changes associated with global motions from molecular dynamics simulations through the use of a Structural Alphabet, which simplifies the complexity of the Cartesian space by reducing the dimensionality down to a string of encoded fragments, representing sets of internal coordinates that still capture the overall conformation changes. In this work, we present "AllohubPy," an improved and standardized methodology of AlloHubMat and GSAtools coded in Python. We analyse the performance, limitations and sampling requirements of AllohubPy by using extensive molecular dynamics simulations of model allosteric systems and apply convergence analysis techniques to estimate result reliability. Additionally, we expand the methodology to use different dimensionality reduction Structural Alphabets, such as the 3DI alphabet, and integrate Protein Language Models (PLMs) to refine allosteric hub communication detection by monitoring the detected evolutionary constraints. Overall, AllohubPy expands its preceding methods and simplifies the use and reliability of the method to effectively capture dynamic allosteric motions and residue pathways. AllohubPy is freely available on GitHub (https://github.com/Fraternalilab/AlloHubPy) as a package and as a Jupyter Notebook.