Fast and Accurate Estimation of Gas-Phase Entropy from the Molecular Surface Curvature

Abstract

Estimating entropy is crucial for understanding and modifying biological systems, such as protein-ligand binding. Current computational methods to estimate entropy require extensive, or at times prohibitively extensive, computational resources. This article presents SHAPE (SHape-based Accurate Predictor of Entropy), a new method that estimates the gas-phase entropy of small molecules purely from their surface geometry. The gas-phase entropy of small molecules can be computed in {approx}0.01 CPU hours with run time complexity of [Formula], where Na is the number of atoms. The accuracy of SHAPE is within 1 - 2% of computationally expensive quantum mechanical or molecular mechanical calculations. We further show that the inclusion of gas-phase entropy, estimated using SHAPE, improves the rank-order correlation between binding affinity and binding score from 0.18 to 0.40. The speed and accuracy of SHAPE make it well-suited for inclusion in molecular docking or QSAR (quantitative structure-activity relationships) methods. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/445640v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1cc10d1org.highwire.dtl.DTLVardef@6448d6org.highwire.dtl.DTLVardef@1e9e308org.highwire.dtl.DTLVardef@385eb2_HPS_FORMAT_FIGEXP M_FIG C_FIG