Population Analysis and Electron Densities from Quantum Mechanics

Bachrach, Steven M.

doi:10.1002/9780470125823.ch3

Cited by 137 publications

(52 citation statements)

References 104 publications

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“…Nevertheless, it is difficult to ascertain the individual atomic charge in a molecule, because generally charge density is not spherical. There have been many varied attempts to derive partial atomic charges [1]. Some are rapid and others are computationally demanding.…”

Section: The Importance Of Partial Charges In Three-dimensional Quantmentioning

confidence: 99%

Various atomic charge calculation schemes of CoMFA on HIF‐1 inhibitors of moracin analogs

Madhavan

Gadhe

Kothandan

et al. 2011

Int J of Quantum Chemistry

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Selection of appropriate partial charges in a molecule is crucial to derive good quantitative structure-activity relationship models. In this work, several partial atomic charges were assigned and tested in a comparative molecular field analysis (CoMFA) models. Many CoMFA models were generated for a series of hypoxia inducible factor 1 (HIF-1) inhibitors using various partial atomic charges including charge equalization, Mü lliken population analysis (MPA), natural population analysis, and electrostatic potential (ESP)-derived charges. These atomic charges were investigated at various theoretical levels such as empirical, semiempirical, Hartree-Fock (HF), and density functional theory (DFT). Among them, Merz-Singh-Kollman (MK) ESP-derived charges at the level of HF/6-31G* gave the highest predictive q 2 with experimental pIC 50 values. With this charge scheme, a detailed analysis of CoMFA model was performed to understand the electrostatic interactions between ligand and receptor. More elaborate charge calculation schemes such as HF and DFT correlated more strongly with activity than empirical or semiempirical schemes. The choice of optimization methods was important. As geometries were fully optimized at the given levels of theory, the aligned structures were different. They differed considerably, especially for the flexible parts. This was likely the source of the substantial variation of q 2 values, even when the same steric factor was considered without electrostatic parameters. ESP-derived charges were most appropriate to describe CoMFA

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Section: The Importance Of Partial Charges In Three-dimensional Quantmentioning

confidence: 99%

Various atomic charge calculation schemes of CoMFA on HIF‐1 inhibitors of moracin analogs

Madhavan

Gadhe

Kothandan

et al. 2011

Int J of Quantum Chemistry

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“…Each of the three free energies in Eqn. (2) should in principle be calculated from an individual simulation, but it is more common to simulate only the complex and then calculate all three free energies in Eqn. 2 from this simulation Swanson et al, 2004).…”

Section: The Mm/pbsa Approachmentioning

confidence: 99%

“…The averages in Eqn. (2) are calculated from a set of snapshots extracted from a molecular dynamics simulation to include the effects of dynamics. Each of the three free energies in Eqn.…”

Section: The Mm/pbsa Approachmentioning

confidence: 99%

Estimates of ligand-binding affinities supported by quantum mechanical methods

Söderhjelm

Kongsted

Genheden

et al. 2010

Interdiscip Sci Comput Life Sci

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In this paper, we review our efforts to use quantum mechanical (QM) methods to improve free-energy estimates of the binding of drug candidates to their receptor proteins. First, we have tested the influence of various implicit solvation models on predictions of the ligand-binding affinity. The accuracy of implicit solvation models strongly depend on the parameterisation, but also on the magnitude of the solvation energy (i.e. their accuracy should be discussed in relative terms). However, if only relative solvation energies within a series of similar drug molecules with the same net charge are considered, nearly all methods tested give a comparable accuracy of 2-5 kJ/mol. Second, we have studied the conformational dependence of QM charges and their influence on ligand-binding affinities. The conformational dependence is significant, but it is to a large extent cancelled by solvation energies. Third, we have estimated the effect and range of electrostatic interactions beyond a point-charge model. The results show that multipoles up to octupoles and anisotropic polarisabilities have a significant influence on energies for residues up to 10-15 A from the ligand and that different sets of point-charge models may give strongly varying results. However, if only relative energies are considered, the effect is to a large extent cancelled. Fourth, we have tried to develop an accurate QM-based molecular mechanics potential, in which not only the electrostatic terms are improved, but also the dispersion and repulsion. However, even with quite sophisticated expressions, it seems difficult to reduce the average error below 2-3 kJ/mol per interaction (e.g. a hydrogen bond), compared to the full QM treatment. Finally, we have developed a new method, PMISP (polarised multipole interaction with supermolecular pairs), for the calculation of accurate interaction energies. It employs an accurate force field for electrostatics and induction, including multipoles up to octupoles and anisotropic polarisabilities calculated by QM methods on amino-acid fragments of the protein in each conformation observed in snapshots from a molecular dynamics simulation, whereas short-range interactions are estimated by high-level QM calculations for all pairs of the ligand with near-by residues. We show that this approach allows us to go far beyond the current accuracy of molecular mechanics methods, down to an error of 5-10 kJ/mol for a full protein-ligand complex. It can be combined with estimates of solvation, entropy, and dynamic effects to give estimates of binding affinities. However, several problems remain to be solved before any significant improvement in the accuracy can be seen.

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“…Another possible scenario for quantum chemistry is to obtain new kinds of molecular descriptors that are not observables, i.e., for which no unique operator can be drawn from the classic-quantum correspondence principle for operators. Good examples of such descriptors are atomic charges 35,36 or several interesting quantities from conceptual density functional theory 37 (DFT). In both cases, quantum chemistry is often a black box, capable of filling holes in the existing dataset for the problem at hand.…”

Section: Basic Elements Of Molecular Similaritymentioning

confidence: 99%