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Comprehensive Assessment of Torsional Strain in Crystal Structures of Small Molecules and Protein–Ligand Complexes using ab Initio Calculations
journal contribution
posted on 2019-10-16, 12:06 authored by Brajesh K. Rai, Vishnu Sresht, Qingyi Yang, Ray Unwalla, Meihua Tu, Alan M. Mathiowetz, Gregory A. BakkenThe
energetics of rotation around single bonds (torsions) is a
key determinant of the three-dimensional shape that druglike molecules
adopt in solution, the solid state, and in different biological environments,
which in turn defines their unique physical and pharmacological properties.
Therefore, accurate characterization of torsion angle preference and
energetics is essential for the success of computational drug discovery
and design. Here, we analyze torsional strain in crystal structures
of druglike molecules in Cambridge structure database (CSD) and bioactive
ligand conformations in protein data bank (PDB), expressing the total
strain energy as a sum of strain energy from constituent rotatable
bonds. We utilized cloud computing to generate torsion scan profiles
of a very large collection of chemically diverse neutral fragments
at DFT(B3LYP)/6-31G*//6-31G** or DFT(B3LYP)/6-31+G*//6-31+G** (for
sulfur-containing molecule). With the data generated from these ab
initio calculations, we performed rigorous analysis of strain due
to deviation of observed torsion angles relative to their ideal gas-phase
geometries. Contrary to the previous studies based on molecular mechanics,
we find that in the crystalline state, molecules generally adopt low-strain
conformations, with median per-torsion strain energy in CSD and PDB
under one-tenth and one-third of a kcal/mol, respectively. However,
for a small fraction (<5%) of motifs, external effects such as
steric hindrance and hydrogen bonds result in strain penalty exceeding
2.5 kcal/mol. We find that due to poor quality of PDB structures in
general, bioactive structures tend to have higher torsional strain
compared to small-molecule crystal conformations. However, in the
absence of structural fitting artifacts in PDB structures, protein-induced
strain in bioactive conformations is quantitatively similar to those
due to the packing forces in small-molecule crystal structures. This
analysis allows us to establish strain energy thresholds to help identify
biologically relevant conformers in a given ensemble. The work presented
here is the most comprehensive study to date that demonstrates the
utility and feasibility of gas-phase quantum mechanics (QM) calculations
to study conformational preference and energetics of drug-size molecules.
Potential applications of this study in computational lead discovery
and structure-based design are discussed.
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protein data bankCambridge structure databasePDB structuresgas-phase quantum mechanicsbioactive ligand conformationsstrain energy thresholdssmall-molecule crystal conformationstorsion scan profilesconstituent rotatable bondstorsion angle preferencedruglike moleculesCSDstrain energyper-torsion strain energyab Initio Calculationshydrogen bonds resultDFTab initio calculationssmall-molecule crystal structurestorsional strainQM
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