PDB Ligand Conformational Energies Calculated Quantum-Mechanically

We present here a greatly updated version of an earlier
study on the conformational energies of protein–ligand complexes
in the Protein Data Bank (PDB) [Nicklaus et al. Bioorg. Med.
Chem. 1995, 3, 411–428],
with the goal of improving on all possible aspects such as number
and selection of ligand instances, energy calculations performed,
and additional analyses conducted. Starting from about 357,000 ligand
instances deposited in the 2008 version of the Ligand Expo database
of the experimental 3D coordinates of all small-molecule instances
in the PDB, we created a “high-quality” subset of ligand
instances by various filtering steps including application of crystallographic
quality criteria and structural unambiguousness. Submission of 640
Gaussian 03 jobs yielded a set of about 415 successfully concluded runs.
We used a stepwise optimization of internal degrees of freedom at
the DFT level of theory with the B3LYP/6-31G­(d) basis set and a single-point
energy calculation at B3LYP/6-311++G­(3df,2p) after each round of (partial)
optimization to separate energy changes due to bond length stretches
vs bond angle changes vs torsion changes. Even for the most “conservative”
choice of all the possible conformational energiesthe energy
difference between the conformation in which all internal degrees
of freedom except torsions have been optimized and the fully optimized
conformersignificant energy values were found. The range of
0 to ∼25 kcal/mol was populated quite evenly and independently
of the crystallographic resolution. A smaller number of “outliers”
of yet higher energies were seen only at resolutions above 1.3 Å.
The energies showed some correlation with molecular size and flexibility
but not with crystallographic quality metrics such as the Cruickshank
diffraction-component precision index (DPI) and Rfree-R,
or with the ligand instance-specific metrics such as occupancy-weighted
B-factor (OWAB), real-space R factor (RSR), and real-space correlation
coefficient (RSCC). We repeated these calculations with the solvent
model IEFPCM, which yielded energy differences that were generally
somewhat lower than the corresponding vacuum results but did not produce
a qualitatively different picture. Torsional sampling around the crystal
conformation at the molecular mechanics level using the MMFF94s force
field typically led to an increase in energy.