Computational Methods for Configurational Entropy Using Internal and Cartesian Coordinates

The configurational entropy of solute molecules is a crucially important quantity to study various biophysical processes. Consequently, it is necessary to establish an efficient quantitative computational method to calculate configurational entropy as accurately as possible. In the present paper, we investigate the quantitative performance of the quasi-harmonic and related computational methods, including widely used methods implemented in popular molecular dynamics (MD) software packages, compared with the Clausius method, which is capable of accurately computing the change of the configurational entropy upon temperature change. Notably, we focused on the choice of the coordinate systems (i.e., internal or Cartesian coordinates). The Boltzmann-quasi-harmonic (BQH) method using internal coordinates outperformed all the six methods examined here. The introduction of improper torsions in the BQH method improves its performance, and anharmonicity of proper torsions in proteins is identified to be the origin of the superior performance of the BQH method. In contrast, widely used methods implemented in MD packages show rather poor performance. In addition, the enhanced sampling of replica-exchange MD simulations was found to be efficient for the convergent behavior of entropy calculations. Also in folding/unfolding transitions of a small protein, Chignolin, the BQH method was reasonably accurate. However, the independent term without the correlation term in the BQH method was most accurate for the folding entropy among the methods considered in this study, because the QH approximation of the correlation term in the BQH method was no longer valid for the divergent unfolded structures