Formal Estimation of Errors in Computed Absolute Interaction Energies of Protein−Ligand Complexes

Faver, John C.; Benson, Mark L.; He, Xiao; Roberts, Benjamin P.; Wang, Bing; Marshall, M. Scott; Kennedy, Matthew R.; Sherrill, C. David; Merz, Kenneth M.

doi:10.1021/ct100563b

Cited by 136 publications

(163 citation statements)

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“…10 The binding pocket was decomposed previously into a total of 21 fragments by Faver et al in their recent study, 25 for which the enzyme-ligand complex structure was obtained from the PDB, hydrogen atoms were added to the structure with the program Reduce 28 and were subsequently optimized with the AMBER FF99SB force field. 29 These 21 receptor fragments and the ligand were combined to model the binding site.…”

Section: Methodsmentioning

confidence: 99%

“…24) meta-GGA (generalized gradient approximation) functional is such an appropriate level of theory. 25 Even in conjunction with the 6-31G* basis set 26 it yielded a narrow error distribution for the bound Indinavir system. We note that in spite of its relative accuracy and speed the M06-L functional has difficulty with convergence for charged systems.…”

Section: Introductionmentioning

confidence: 99%

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Pairwise additivity of energy components in protein-ligand binding: The HIV II protease-Indinavir case

Ucisik

Dashti

Faver

et al. 2011

The Journal of Chemical Physics

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An energy expansion (binding energy decomposition into n-body interaction terms for n ≥ 2) to express the receptor-ligand binding energy for the fragmented HIV II protease-Indinavir system is described to address the role of cooperativity in ligand binding. The outcome of this energy expansion is compared to the total receptor-ligand binding energy at the Hartree-Fock, density functional theory, and semiempirical levels of theory. We find that the sum of the pairwise interaction energies approximates the total binding energy to ∼82% for HF and to >95% for both the M06-L density functional and PM6-DH2 semiempirical method. The contribution of the three-body interactions amounts to 18.7%, 3.8%, and 1.4% for HF, M06-L, and PM6-DH2, respectively. We find that the expansion can be safely truncated after n = 3. That is, the contribution of the interactions involving more than three parties to the total binding energy of Indinavir to the HIV II protease receptor is negligible. Overall, we find that the two-body terms represent a good approximation to the total binding energy of the system, which points to pairwise additivity in the present case. This basic principle of pairwise additivity is utilized in fragment-based drug design approaches and our results support its continued use. The present results can also aid in the validation of non-bonded terms contained within common force fields and in the correction of systematic errors in physics-based score functions.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pairwise additivity of energy components in protein-ligand binding: The HIV II protease-Indinavir case

Ucisik

Dashti

Faver

et al. 2011

The Journal of Chemical Physics

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“…292 The 3B-69 data set is of particular interest to the discussion here, as it benchmarks molecular three-body contributions to interactions energies. 293 An interesting approach was used by Faver et al, 294 who dissected a protein−ligand complex 1HSG into 21 smaller fragment dimers bound by noncovalent interactions.…”

Section: Benchmark Databasesmentioning

confidence: 99%

First-Principles Models for van der Waals Interactions in Molecules and Materials: Concepts, Theory, and Applications

2017

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Noncovalent van der Waals (vdW) or dispersion forces are ubiquitous in nature and influence the structure, stability, dynamics, and function of molecules and materials throughout chemistry, biology, physics, and materials science. These forces are quantum mechanical in origin and arise from electrostatic interactions between fluctuations in the electronic charge density. Here, we explore the conceptual and mathematical ingredients required for an exact treatment of vdW interactions, and present a systematic and unified framework for classifying the current first-principles vdW methods based on the adiabatic-connection fluctuation−dissipation (ACFD) theorem (namely the Rutgers−Chalmers vdW-DF, Vydrov−Van Voorhis (VV), exchange-hole dipole moment (XDM), Tkatchenko−Scheffler (TS), many-body dispersion (MBD), and random-phase approximation (RPA) approaches). Particular attention is paid to the intriguing nature of many-body vdW interactions, whose fundamental relevance has recently been highlighted in several landmark experiments. The performance of these models in predicting binding energetics as well as structural, electronic, and thermodynamic properties is connected with the theoretical concepts and provides a numerical summary of the state-of-the-art in the field. We conclude with a roadmap of the conceptual, methodological, practical, and numerical challenges that remain in obtaining a universally applicable and truly predictive vdW method for realistic molecular systems and materials.

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“…While PARI-K yields impressive accuracy in its own right, the accuracy of occ-RI-K is clearly superior. The errors per electron in the absolute energies of all molecules in the test set are quite 73,74 0.00 0.00 Butanediol65 75 0.00 0.00 BzDC215 76 0.00 0.00 CT20 77 0.00 0.00 DIE60 78 0.00 0.00 DS14 79 0.00 0.01 EA13 80 0.01 0.01 EIE22 81 0.00 0.00 FmH2O10 82,83 0.01 0.16 ACONF 84,85 0.00 0.01 BHPERI 85,86 0.00 0.00 CYCONF 85,87 0.00 0.00 G21EA 85,88 0.00 0.00 G21IP 85,88 0.00 0.00 NBPRC 85 0.00 0.02 WATER27 85,89 0.00 0.03 NHTBH38 85,90 0.01 0.02 HTBH38 85,91 0.00 0.01 BH76RC 85 0.00 0.00 DBH24 86 0.00 0.01 H2O6Bind8 83,92 0.00 0.05 HB15 93 0.00 0.01 HSG 94,95 0.00 0.00 HW30 96 0.00 0.01 HW6Cl 82,83 0.00 0.04 HW6F 82,83 0.00 0.04 IP13 80 0.00 0.00 NBC10 95 0.01 0.01 NC15 97 0.00 0.00 Pentane14 98 0.00 0.01 RG10 99 0.00 0.00 S22 …”

Section: A Accuracymentioning

confidence: 99%

Fast, accurate evaluation of exact exchange: The occ-RI-K algorithm

Manzer

Horn

Mardirossian

et al. 2015

The Journal of Chemical Physics

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Construction of the exact exchange matrix, K, is typically the rate-determining step in hybrid density functional theory, and therefore, new approaches with increased efficiency are highly desirable. We present a framework with potential for greatly improved efficiency by computing a compressed exchange matrix that yields the exact exchange energy, gradient, and direct inversion of the iterative subspace (DIIS) error vector. The compressed exchange matrix is constructed with one index in the compact molecular orbital basis and the other index in the full atomic orbital basis. To illustrate the advantages, we present a practical algorithm that uses this framework in conjunction with the resolution of the identity (RI) approximation. We demonstrate that convergence using this method, referred to hereafter as occupied orbital RI-K (occ-RI-K), in combination with the DIIS algorithm is well-behaved, that the accuracy of computed energetics is excellent (identical to conventional RI-K), and that significant speedups can be obtained over existing integral-direct and RI-K methods. For a 4400 basis function C 68 H 22 hydrogen-terminated graphene fragment, our algorithm yields a 14× speedup over the conventional algorithm and a speedup of 3.3× over RI-K. C 2015 AIP Publishing LLC. [http://dx

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Formal Estimation of Errors in Computed Absolute Interaction Energies of Protein−Ligand Complexes

Cited by 136 publications

References 53 publications

Pairwise additivity of energy components in protein-ligand binding: The HIV II protease-Indinavir case

Pairwise additivity of energy components in protein-ligand binding: The HIV II protease-Indinavir case

First-Principles Models for van der Waals Interactions in Molecules and Materials: Concepts, Theory, and Applications

Fast, accurate evaluation of exact exchange: The occ-RI-K algorithm

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