Molecular recognition mechanism of FK506 binding protein: An all‐electron fragment molecular orbital study

Nakanishi, Isao; Fedorov, Dmitri G.; Kitaura, Kazuo

doi:10.1002/prot.21389

Cited by 76 publications

(95 citation statements)

References 58 publications

(59 reference statements)

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“…Finally, for completeness, it is useful to separate 518 the sum of the polarization and deformations energies given by the difference in the energy of the protein or ligand in the complexed and isolated states.…”

Section: δEmentioning

confidence: 99%

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Fragmentation Methods: A Route to Accurate Calculations on Large Systems

et al. 2011

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Theoretical chemists have always strived to perform quantum mechanics (QM) calculations on larger and larger molecules and molecular systems, as well as condensed phase species, that are frequently much larger than the current state-of-the-art would suggest is possible. The desire to study species (with acceptable accuracy) that are larger than appears to be feasible has naturally led to the development of novel methods, including semiempirical approaches, reduced scaling methods, and fragmentation methods. The focus of the present review is on fragmentation methods, in which a large molecule or molecular system is made more computationally tractable by explicitly considering only one part (fragment) of the whole in any particular calculation. If one can divide a species of interest into fragments, employ some level of ab initio QM to calculate the wave function, energy, and properties of each fragment, and then combine the results from the fragment calculations to predict the same properties for the whole, the possibility exists that the accuracy of the outcome can approach that which would be obtained from a full (nonfragmented) calculation. It is this goal that drives the development of fragmentation methods. Disciplines Chemistry CommentsReprinted (adapted) with permission from Chemical Reviews 112 (2012): 632,

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Section: δEmentioning

confidence: 99%

“…The stabilizing polarization (pols) and charge transfer, as well as other types of interactions are included in the sum of the proteinÀligand PIEs ΔE PL . The former can be estimated 518 using the simple response relation ΔE A pols ≈ À2ΔE A pold (see actual calculations 300 for numerical justification), which leads to the total polarization…”

Section: δEmentioning

confidence: 99%

Fragmentation Methods: A Route to Accurate Calculations on Large Systems

et al. 2011

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“…Such methods are typically based on either semiempirical calculations [6,7] or on higher-level methods, based on fractionation approaches, e.g. the fragment molecular orbital method (FMO) [8,9] or the molecular fractionation with conjugate caps (MFCC) and related methods [10,11,12,13,14,15,16]. It is well-known that calculations of dispersion effects generally require a very high level of theory [17].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, the effects of the surrounding solvent, entropy, and sampling need to be taken into account [1,4]. Only a few of the previous studies take into account effects of solvation [6,7,9] and entropy [6,7], and none of them consider sampling.…”

Section: Introductionmentioning

confidence: 99%

Ligand Affinities Estimated by Quantum Chemical Calculations

Söderhjelm

Kongsted

Ryde

2010

J. Chem. Theory Comput.

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We present the first fully quantum chemical estimates of ligand-binding affinities, performed at a reasonable level of theory (MP2/cc-pVTZ) and at the same time including all physically important effects, such as solvation, entropy, and sampling. We have studied the binding of seven biotin analogues to the avidin tetramer. The calculations have been performed by the recently developed PMISP approach (polarisable multipole interactions with supermolecular pairs), which treats electrostatic interactions by multipoles up to quadrupoles, induction by anisotropic polarisabilities, and non-classical interactions (dispersion, exchange repulsion, etc.) by explicit quantum chemical calculations, using a fragmentation approach, except for long-range interactions, which are treated by standard molecular mechanics LennardJones terms. In order to include effects of sampling, ten snapshots from a molecular dynamics simulation are studied for each complex. Solvation energies are estimated by a polarised continuum model (PCM), coupled to the multipole-polarisability model. Entropy effects are estimated from vibrational frequencies, calculated at the molecular mechanics level. We encounter several problems, not previously discussed, illustrating that we are first to apply such a method. For example, the PCM model is questionable for large molecules, owing to the use of a surface definition that gives numerous small cavities in a protein. IntroductionA major goal of theoretical chemistry is to accurately predict the free energy for the binding of a ligand to a macromolecule. If such binding affinities could be accurately predicted, large parts of the drug development could be performed by computer simulations rather than by costly experiments, because essentially all drugs evoke their action by binding to a target macromolecule. Likewise, many interesting questions in biochemistry can be formulated as the differential binding affinities of a substrate, product, or transition-state to a protein or enzyme.

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“…The FMO method has been applied to a number of large systems. [53][54][55][56][57][58][59][60][61][62][63][64][65][66] FMO-MD has been used [67][68][69][70][71][72][73][74][75][76][77][78] to study the dynamics of various processes such as chemical reactions. However, the FMO-MD method suffers from an accumulation of errors 67 with the time evolution due to an incomplete analytic FMO energy gradient.…”

Section: Introductionmentioning

confidence: 99%

Fully analytic energy gradient in the fragment molecular orbital method

Brorsen¹,

Fedorov²

2011

The Journal of Chemical Physics

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The Z-vector equations are derived and implemented for solving the response term due to the external electrostatic potentials, and the corresponding contribution is added to the energy gradients in the framework of the fragment molecular orbital (FMO) method. To practically solve the equations for large molecules like proteins, the equations are decoupled by taking advantage of the local nature of fragments in the FMO method and establishing the self-consistent Z-vector method. The resulting gradients are compared with numerical gradients for the test molecular systems: (H 2 O) 64 , alanine decamer, hydrated chignolin with the protein data bank (PDB) ID of 1UAO, and a Trp-cage miniprotein construct (PDB ID: 1L2Y). The computation time for calculating the response contribution is comparable to or less than that of the FMO selfconsistent charge calculation. It is also shown that the energy gradients for the electrostatic dimer approximation are fully analytic, which significantly reduces the computational costs. The fully analytic FMO gradient is parallelized with an efficiency of about 98% on 32 nodes. KeywordsPolymers, Electrostatics, Chemical bonds, Proteins, Density functional theory Disciplines Chemistry CommentsThe following article appeared in Journal of Chemical Physics 134 (2011) The Z-vector equations are derived and implemented for solving the response term due to the external electrostatic potentials, and the corresponding contribution is added to the energy gradients in the framework of the fragment molecular orbital (FMO) method. To practically solve the equations for large molecules like proteins, the equations are decoupled by taking advantage of the local nature of fragments in the FMO method and establishing the self-consistent Z-vector method. The resulting gradients are compared with numerical gradients for the test molecular systems: (H 2 O) 64 , alanine decamer, hydrated chignolin with the protein data bank (PDB) ID of 1UAO, and a Trp-cage miniprotein construct (PDB ID: 1L2Y). The computation time for calculating the response contribution is comparable to or less than that of the FMO self-consistent charge calculation. It is also shown that the energy gradients for the electrostatic dimer approximation are fully analytic, which significantly reduces the computational costs. The fully analytic FMO gradient is parallelized with an efficiency of about 98% on 32 nodes.

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Molecular recognition mechanism of FK506 binding protein: An all‐electron fragment molecular orbital study

Cited by 76 publications

References 58 publications

Fragmentation Methods: A Route to Accurate Calculations on Large Systems

Fragmentation Methods: A Route to Accurate Calculations on Large Systems

Ligand Affinities Estimated by Quantum Chemical Calculations

Fully analytic energy gradient in the fragment molecular orbital method

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