Free energy calculations in globular proteins: Methods to reduce errors

Nola, Alfredo Di; Brünger, A.T.

doi:10.1002/(sici)1096-987x(199808)19:11<1229::aid-jcc3>3.0.co;2-m

Cited by 6 publications

(3 citation statements)

References 32 publications

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“…Firstly, the molecular model and the force field used to describe the system thermodynamics must yield realistic probabilities for its most representative conformations. Secondly, low frequency motions and long time relaxations of the system must be handled properly to obtain a fair sampling of the relevant conformational space [33]. This is often done by restricting the number of degrees of freedom chosen to model the system but such a choice then affects the sets of sampled conformations.…”

Section: Introductionmentioning

confidence: 99%

Contribution of both catalytic constant and Michaelis constant to CALB enantioselectivity: Use of FEP calculations for prediction studies

Chaput

Sanejouand

Balloumi

et al. 2012

Journal of Molecular Catalysis B: Enzymatic

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Candida antarctica lipase B (CALB) is characterised by its stability and ease of production and is widely used in the pharmaceutical industry. Here we report on the enantioselectivity of the enzyme using both experimental and computational methods. The apparent kinetic parameters were first experimentally determined for enantiopure butan-2-ol and pentan-2-ol substrates. We demonstrate that enantiopreference for the R form of butan-2-ol arises mainly from a lower apparent K M . This corresponds to a major contribution of ∆∆G ES , the free energy difference between the ES complex formed with the R and S enantiomers, to ∆∆G ‡ , the free energy difference between both transition states, in comparison with ∆∆G kcat , the activation free energy difference. In the case of pentan-2-ol, we show that the enantiopreference for the R form comes from both a lower K M and a higher k cat . In addition, we used, for the first time, the Free Energy Perturbation method to evaluate the free energy difference between tetrahedral intermediates formed with R and S alcohol enantiomers for a series of secondary alcohols . This is a valid model for ∆∆G ‡ . Computational results were found to be in good agreement with experimental data, and enable the determination of substrate orientation in the active site with fair confidence.

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Section: Introductionmentioning

confidence: 99%

Contribution of both catalytic constant and Michaelis constant to CALB enantioselectivity: Use of FEP calculations for prediction studies

Chaput

Sanejouand

Balloumi

et al. 2012

Journal of Molecular Catalysis B: Enzymatic

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“…Among them one of the most interesting is the calculation of conformational equilibria of a molecule in the gas phase and in solution which is in general still quite unfeasible, mainly because of the difficulty in estimating the free energies involved. Computer simulation techniques, such as molecular mechanics (MM), − molecular dynamics (MD), − and Monte Carlo (MC), have been used extensively to calculate conformational equilibria, and specialized sampling techniques, such as umbrella sampling, thermodynamic perturbation (TP), and thermodynamic integration (TI), coupled to MD or MC have been used both in gas and liquid phases to evaluate the Helmholtz free energy differences due to configurational changes. For small molecules, the internal energy evaluation is straightforward in the gas phase and still possible in solution using nonquantum mechanical approaches.…”

Section: Introductionmentioning

confidence: 99%

“…For small molecules, the internal energy evaluation is straightforward in the gas phase and still possible in solution using nonquantum mechanical approaches. More difficulties can arise in the calculation of the entropic contribution to the free energy, due to poor convergence of the calculations . In addition, the prediction of the temperature dependence of conformational equilibria is still done on empirical basis, e.g.…”

Section: Introductionmentioning

confidence: 99%

On the Use of the Quasi-Gaussian Entropy Theory in Systems of Polyatomic Flexible Molecules

et al. 2001

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In this article we show how the quasi-Gaussian entropy (QGE) theory can be used to treat systems of polyatomic flexible molecules, where the usual semirigid description is not always appropriate. We describe a completely general derivation of the QGE theory which does not make use of any semirigid approximation, and therefore it is very suited for large and flexible molecules. Using molecular dynamics simulations of flexible molecules in vacuo, we investigated the ability of the theory to describe intramolecular energy fluctuations and conformational equilibria of purely classical molecules in the ideal gas condition. Results show that the gamma state level of the theory and its generalization for treating conformational equilibria (multi-gamma state model) provide excellent theoretical models when applied to three polyatomic molecules of increasing conformational freedom.

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Effects of core-packing on the structure, function, and mechanics of a four-helix-bundle protein ROP

1999

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The effects of core-packing on the structure, function and mechanics of the RNA-binding 4-helix-bundle Rop have been studied by molecular dynamics simulations. The structural, dynamical and geometrical properties of the Rop homodimer, (formed by the antiparallel juxtaposition of two helix-turn-helix motifs), have been compared with those of three protein variants described by Munson et al. (Protein Sci, 5:1584-1593, 1996), where the core of the native protein has been systematically repacked using a two-amino acid alphabet: Ala(2)Leu(2)-8, Ala(2)Leu(2)-8-rev, and Leu(2)Ala(2)-8. The results showed that it was possible to readily distinguish the inactive protein Leu(2)Ala(2)-8 from the other functionally active systems based on tertiary and quaternary structure criteria. Structural properties such as native secondary structure content did not correlate with biological activity. Biological activity was related in part to the relative arrangement of the residues within the binding site. But, more global aspects, related to the overall topology of the helical bundle, accounted for the small functional differences between Ala(2)Leu(2)-8 and Ala(2)Leu(2)-8-rev. Mechanically, the 4-helix-bundle absorbed core mutations by altering the local structure at the sequence termini and in the turns that join the two helices of each monomer, and by changing the overall orientation and separation of the extremely rigid helices. Proteins 1999;36:436-446.

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Free energy calculations in globular proteins: Methods to reduce errors

Cited by 6 publications

References 32 publications

Contribution of both catalytic constant and Michaelis constant to CALB enantioselectivity: Use of FEP calculations for prediction studies

Contribution of both catalytic constant and Michaelis constant to CALB enantioselectivity: Use of FEP calculations for prediction studies

On the Use of the Quasi-Gaussian Entropy Theory in Systems of Polyatomic Flexible Molecules

Effects of core-packing on the structure, function, and mechanics of a four-helix-bundle protein ROP

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