Abstract
AbstractWe have performed a large‐scale evaluation of current computational methods, including conventional small‐molecule force fields; semiempirical, density functional, ab initio electronic structure methods; and current machine learning (ML) techniques to evaluate relative single‐point energies. Using up to 10 local minima geometries across ~700 molecules, each optimized by B3LYP‐D3BJ with single‐point DLPNO‐CCSD(T) triple‐zeta energies, we consider over 6500 single points to compare the correlation between different methods for both relative energies and ordered rankings of minima. We find that the current ML methods have potential and recommend methods at each tier of the accuracy‐time tradeoff, particularly the recent GFN2 semiempirical method, the B97‐3c density functional approximation, and RI‐MP2 for accurate conformer energies. The ANI family of ML methods shows promise, particularly the ANI‐1ccx variant trained in part on coupled‐cluster energies. Multiple methods suggest continued improvements should be expected in both performance and accuracy.
Highlights
For almost all molecules, multiple geometrically-distinct conformers exist
We focus on the evaluation of single point atomization energy calculations on a subset of ~700 organic molecules
Conformers were initially created from a set of 250 diverse poses with maximal heavy-atom root mean squared deviation (RMSD) using Open Babel, and at most 10 poses were selected based on the lowest heat of formation calculated by PM7, followed by full geometry optimization using B3LYP-D3BJ with the def2-SVP basis set.[59]
Summary
Multiple geometrically-distinct conformers exist. Understanding and predicting thermodynamically accessible ensembles of molecular conformers is a key task underlying much of computational chemistry.[26, 72, 52] In principle, for each rotatable bond, the number of possible minima increases exponentially. 102 104 msec Time (s) hrs days most conformer sampling methods[45] use classical small-molecule force fields to evaluate energies because of their fast performance, despite potentially poor correlation with quantum mechanical methods.[59]. Multiple efforts have evaluated the success of wavefunction and density functional first-principles methods to compare the energetics of different conformers.[34, 95, 63, 92, 86, 60, 116] While experimental crystal structures and bioactive docked conformers are not always the lowest energy conformer, recent efforts have demonstrated only small energy differences when using quantum chemical methods instead of force fields.[88, 23]. Journal of Chemical Theory and Computation, 13(5):2043–2052, apr 2017. The Journal of Physical Chemistry A, 118(36):7876–7891, aug 2014
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