Application and Comprehensive Analysis of Neighbor Approximated Information Theoretic Configurational Entropy Methods to Protein-Ligand Binding Cases.

The binding entropy is an important thermodynamic quantity which has numerous applications in studies of the biophysical process, and configurational entropy is often one of the major contributors in it. Therefore, its accurate estimation is important, though it is challenging mostly due to sampling limitations, anharmonicity, and multimodality of atomic fluctuations. The present work reports a Neighbor Approximated Maximum Information Spanning Tree (A-MIST) method for conformational entropy and presents its performance and computational advantage over conventional Mutual Information Expansion (MIE) and Maximum Information Spanning Tree (MIST) for two protein-ligand binding cases: indirubin-5-sulfonate to Plasmodium falciparum Protein Kinase 5 (PfPK5) and P. falciparum RON2-peptide to P. falciparum Apical Membrane Antigen 1 (PfAMA1). Important structural regions considering binding configurational entropy are identified, and physical origins for such are discussed. A thorough performance evaluation is done of a set of four entropy estimators (Maximum Likelihood (ML), Miller-Madow (MM), Chao-Shen (CS), and James and Stein shrinkage (JS)) with known varying degrees of sensitivity of the entropy estimate on the extent of sampling, each with two schemes for discretization of fluctuation data of Degrees of Freedom (DFs) to estimate Probability Density Functions (PDFs). Our comprehensive evaluation of influences of variations of parameters shows Neighbor Approximated MIE (A-MIE) outperforms MIE in terms of convergence and computational efficiency. In the case of A-MIE/MIE, results are sensitive to the choice of root atoms, graph search algorithm used for the Bond-Angle-Torsion (BAT) conversion, and entropy estimator, while A-MIST/MIST are not. A-MIST yields binding entropy within 0.5 kcal/mol of MIST with only 20-30% computation. Moreover, all these methods have been implemented in an OpenMP/MPI hybrid parallel C++11 code, and also a python package for data preprocessing and entropy contribution analysis is developed and made available. A comparative analysis of features of current implementation and existing tools is also presented.