Torsional Energy Barriers of Biaryls Could Be Predicted by Electron Richness/Deficiency of Aromatic Rings; Advancement of Molecular Mechanics toward Atom-Type Independence

Wei, Wanlei; Champion, Candide; Liu, Zhaomin; Barigye, Stephen J.; Labute, Paul; Moitessier, Nicolas

doi:10.1021/acs.jcim.9b00585

Cited by 15 publications

(29 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is well-appreciated that general small molecule MM force fields often fail to accurately describe torsion energy profiles observed with higher-level quantum chemical calculations [73,74], a phenomenon driven by the significant effect substituents can have on torsion profiles via electronic effects [26,75]. To overcome this limitation, many MM force fields recommend refitting torsion potentials directly to quantum chemical calculations for individual molecules in a bespoke manner [1,27].…”

Section: Improved Torsion Energetics Appear To Drive Accuracy Improvementioning

confidence: 99%

Towards chemical accuracy for alchemical free energy calculations with hybrid physics-based machine learning / molecular mechanics potentials

Rufa

Macdonald

Fass

et al. 2020

Preprint

106

View full text Add to dashboard Cite

Alchemical free energy methods with molecular mechanics (MM) force fields are now widely used in the prioritization of small molecules for synthesis in structure-enabled drug discovery projects because of their ability to deliver 1–2 kcal mol−1 accuracy in well-behaved protein-ligand systems. Surpassing this accuracy limit would significantly reduce the number of compounds that must be synthesized to achieve desired potencies and selectivities in drug design campaigns. However, MM force fields pose a challenge to achieving higher accuracy due to their inability to capture the intricate atomic interactions of the physical systems they model. A major limitation is the accuracy with which ligand intramolecular energetics—especially torsions—can be modeled, as poor modeling of torsional profiles and coupling with other valence degrees of freedom can have a significant impact on binding free energies. Here, we demonstrate how a new generation of hybrid machine learning / molecular mechanics (ML/MM) potentials can deliver significant accuracy improvements in modeling protein-ligand binding affinities. Using a nonequilibrium perturbation approach, we can correct a standard, GPU-accelerated MM alchemical free energy calculation in a simple post-processing step to efficiently recover ML/MM free energies and deliver a significant accuracy improvement with small additional computational effort. To demonstrate the utility of ML/MM free energy calculations, we apply this approach to a benchmark system for predicting kinase:inhibitor binding affinities—a congeneric ligand series for non-receptor tyrosine kinase TYK2 (Tyk2)—wherein state-of-the-art MM free energy calculations (with OPLS2.1) achieve inaccuracies of 0.93±0.12 kcal mol−1 in predicting absolute binding free energies. Applying an ML/MM hybrid potential based on the ANI2x ML model and AMBER14SB/TIP3P with the OpenFF 1.0.0 (“Parsley”) small molecule force field as an MM model, we show that it is possible to significantly reduce the error in absolute binding free energies from 0.97 [95% CI: 0.68, 1.21] kcal mol−1 (MM) to 0.47 [95% CI: 0.31, 0.63] kcal mol−1 (ML/MM).

show abstract

Section: Improved Torsion Energetics Appear To Drive Accuracy Improvementioning

confidence: 99%

Towards chemical accuracy for alchemical free energy calculations with hybrid physics-based machine learning / molecular mechanics potentials

Rufa

Macdonald

Fass

et al. 2020

Preprint

106

View full text Add to dashboard Cite

show abstract

“…However, since atom types are locally defined, they do not always capture long-range effects such as conjugation. This is especially problematic for torsions since the torsion energy function (or profile) of a bond is determined by a combination of local and non-local effects such as conjugation, hyperconjugation, sterics, and electrostatics [37,38,39,40,41]. In this study, we define local atoms as those within two bonds of the central bond of a torsion, and remote atoms as any atom beyond those two bonds.…”

Section: Theory and Definitionsmentioning

confidence: 99%

“…Bond orders are correlated with bond vibrational frequencies [28, 50] and WBOs are used to predict trigger bonds in high energy-density material because they are correlated with the strength of bonds [19], a property which also directly affects the torsion potential. Wei et al [48] have shown that simple rules for electron richness of aromatic systems in biaryls are a good indication of torsion force constants (specifically for K ϕ,n in equation 1); however, this measure was only developed for biaryls and it does not take into account substituents beyond the aromatic ring directly adjacent to the bond.…”

Section: Introductionmentioning

confidence: 99%

Capturing non-local through-bond effects in molecular mechanics force fields I: Fragmenting molecules for quantum chemical torsion scans [Article v1.1]

Stern

Bayly²,

Smith

et al. 2020

Preprint

View full text Add to dashboard Cite

Accurate molecular mechanics force fields for small molecules are essential for predicting protein-ligand binding affinities in drug discovery and understanding the biophysics of biomolecular systems. Torsion potentials derived from quantum chemical (QC) calculations are critical for determining the conformational distributions of small molecules, but are computationally expensive and scale poorly with molecular size. To reduce computational cost and avoid the complications of distal through-space intramolecular interactions, molecules are generally fragmented into smaller entities to carry out QC torsion scans. However, torsion potentials, particularly for conjugated bonds, can be strongly affected by through-bond chemistry distal to the torsion itself. Poor fragmentation schemes have the potential to significantly disrupt electronic properties in the region around the torsion by removing important, distal chemistries, leading to poor representation of the parent molecule’s chemical environment and the resulting torsion energy profile. Here we show that a rapidly computable quantity, the fractional Wiberg bond order (WBO), is a sensitive reporter on whether the chemical environment around a torsion has been disrupted. We show that the WBO can be used as a surrogate to assess the robustness of fragmentation schemes and identify conjugated bond sets. We use this concept to construct a validation set by exhaustively fragmenting a set of druglike organic molecules and examine their corresponding WBO distributions derived from accessible conformations that can be used to evaluate fragmentation schemes. To illustrate the utility of the WBO in assessing fragmentation schemes that preserve the chemical environment, we propose a new fragmentation scheme that uses rapidly-computable AM1 WBOs, which are available essentially for free as part of standard AM1-BCC partial charge assignment. This approach can simultaneously maximize the chemical equivalency of the fragment and the substructure in the larger molecule while minimizing fragment size to accelerate QC torsion potential computation for small molecules and reducing undesired through-space steric interactions.

show abstract

“…This can be explained by the increased length of conjugation providing more resonance stabilization, as discussed later. The B.O.>1 observed at ϕ =90° might be a result of hyperconjugation (σ–π*/σ*–π), which can lead to slight stabilization of orthogonal conformations [47a] …”

Section: Resultsmentioning

confidence: 99%

Quantifying Planarity in the Design of Organic Electronic Materials

Che

Perepichka

2020

Angewandte Chemie

View full text Add to dashboard Cite

Planarity is essential for many organic electronic materials as it maximizes the intramolecular p-orbital overlap and enables efficient intermolecular interactions through pstacking. We propose as tatistical way of quantifying the planarity of awide range of conjugated systems.The quantification takes into account all torsional conformations and their relative contribution to the overall structural disorder,through ap lanarity index hcos 2 fi.T he propensity for planarization and the effect of rotational disorder were examined for aseries of commonly used building blocks.T he application of the analysis to extended conjugated systems and the correlations between the gas-phase hcos 2 fi and crystallographically observed planarity in the solid state were explored. Our calculations also reveal ap reviously unrecognized effect of increasing band gap upon planarization for conjugated systems coupling strong electron donor and acceptor units.

show abstract

Torsional Energy Barriers of Biaryls Could Be Predicted by Electron Richness/Deficiency of Aromatic Rings; Advancement of Molecular Mechanics toward Atom-Type Independence

Cited by 15 publications

References 67 publications

Towards chemical accuracy for alchemical free energy calculations with hybrid physics-based machine learning / molecular mechanics potentials

Towards chemical accuracy for alchemical free energy calculations with hybrid physics-based machine learning / molecular mechanics potentials

Capturing non-local through-bond effects in molecular mechanics force fields I: Fragmenting molecules for quantum chemical torsion scans [Article v1.1]

Quantifying Planarity in the Design of Organic Electronic Materials

Contact Info

Product

Resources

About