Q: a molecular dynamics program for free energy calculations and empirical valence bond simulations in biomolecular systems

Marelius, John; Kolmodin, Karin; Feierberg, Isabella; Åqvist, Johan

doi:10.1016/s1093-3263(98)80006-5

Cited by 304 publications

(336 citation statements)

References 51 publications

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“…The protein-ligand complexes and the free ligands were solvated in a sphere of TIP3P 29 water molecules on a grid using a combination of the Q program (version 5), 19 the Amber 10 suite of programs, 30 as well as in-house scripts. First, the complex was fully immersed in a water sphere that extended at least 10 Å outside the protein.…”

Section: Methodsmentioning

confidence: 99%

Improving the Efficiency of Protein–Ligand Binding Free-Energy Calculations by System Truncation

Genheden

Ryde

2012

J. Chem. Theory Comput.

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We have studied whether the efficiency of alchemical free-energy calculations with the Bennett acceptance ratio method of protein-ligand binding energies can be improved by simulating only a part of the protein. To this end, we solvated the full protein in a spherical droplet with a radius of 46 Å, surrounded by vacuum. Then, we systematically reduced the size of the droplet and at the same time ignored protein residues that were outside the droplet. Radii of 40 to 15 Å were tested. Ten inhibitors of the blood clotting factor Xa were studied and the results were compared to an earlier study in which the protein was solvated in a periodic box, showing complete agreement between the two set of calculations within statistical uncertainty. We then show that the simulated system can be truncated down to 15 Å, without changing the calculated affinities by more than 0.5 kJ/mol on average (maximum difference 1.4 kJ/mol). Moreover, we show that reducing the number of intermediate states in the calculations from eleven to three gave deviations that on average were only 0.5 kJ/mol (maximum 1.4 kJ/mol). Together this shows that truncation is an appropriate way to improve efficiency of free-energy calculations for small mutations that preserve the net charge of the ligand. In fact, each calculation of a relative binding affinity requires only 6 simulations, each of which takes ~15 CPU hours of computation on a single processor.Keywords: free-energy perturbation, Bennett acceptance ratio, ligand-binding affinities, periodic boundary conditions, system truncation, long-range electrostatics.2 Introduction Accurate estimation of protein-ligand binding affinities is a major challenge in computational chemistry. Although formally correct relative free energies can be obtained by alchemical free-energy techniques such a free energy perturbation (FEP) and thermodynamic integration (TI), they have found little use outside academia. 1,2 The main reason for this is that such methods are computationally demanding, because they require simulations of unphysical intermediate states involving extensive sampling of the phase space. 3 More approximate methods to estimate binding affinities exists, which do not require simulations of intermediate states. 4 They are usually referred to as end-points methods because they sample only the complex, and possibly the free protein and the free ligand. 5 A popular method in this class is MM/GBSA (molecular mechanics with generalised Born and surface-area solvation). 6,7 Although it only requires a simulation of the complex, we have shown that it can actually be computationally more expensive than TI because it is intrinsically imprecise and requires averaging over many independent simulations to reach a precision comparable to that of FEP or TI. 8 In addition, the accuracy of some of the terms in MM/GBSA have been questioned and the method often fails to give a useful accuracy of the predicted affinities. 9,10,11 Another popular end-point method is the linear interaction energy (LIE). 12 We ...

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Section: Methodsmentioning

confidence: 99%

Improving the Efficiency of Protein–Ligand Binding Free-Energy Calculations by System Truncation

Genheden

Ryde

2012

J. Chem. Theory Comput.

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“…A nonbonded cutoff of 10 Å was used together with multipole expansion for long range electrostatics (18). The water surface was subjected to radial and polarization restraints as described elsewhere (19,20). Net charges were assigned to Arg 37 , Glu 99 , Lys 150 , and Glu 172 because these amino acid residues are close to the reaction center, whereas distant ionizable groups were treated as neutral.…”

Section: Methodsmentioning

confidence: 99%

Computer Simulation of Primary Kinetic Isotope Effects in the Proposed Rate-limiting Step of the Glyoxalase I Catalyzed Reaction

Feierberg

Luzhkov²,

Åqvist

2000

Journal of Biological Chemistry

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The proposed rate-limiting step of the glyoxalase I catalyzed reaction is the proton abstraction from the C1 carbon of the substrate by Glu 172 . Here we examine primary kinetic isotope effects and the influence of quantum dynamics on this process by computer simulations. The calculations utilize the empirical valence bond method in combination with the molecular dynamics free energy perturbation technique and path integral simulations. For the enzyme-catalyzed reaction a H/D kinetic isotope effect of 5.0 ؎ 1.3 is predicted in reasonable agreement with the experimental result of about 3. Furthermore, the magnitude of quantum mechanical effects is found to be very similar for the enzyme reaction and the corresponding uncatalyzed process in solution, in agreement with other studies. The problems associated with attaining the required accuracy in order for the present approach to be useful as a diagnostic tool for the study of enzyme reactions are also discussed.

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“…All MD simulations were run using the software package Q [9] 0014-5793 / 00 / $20. together with the GROMOS87 force ¢eld [10].…”

Section: Methodsmentioning

confidence: 99%

“…The active site of the enzyme was solvated by a 16 A î sphere of SPC water molecules. The solvent surface was subjected to radial and polarisational restraints as described in [9]. Protein atoms outside the simulation sphere were restrained to their crystallographic coordinates and interacted only via bonds, angles and torsions across the boundary.…”

Section: Methodsmentioning

confidence: 99%

Prediction of a ligand‐induced conformational change in the catalytic core of Cdc25A

Kolmodin

Åqvist

1999

FEBS Letters

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The cell cycle control phosphatases Cdc25 are dual specificity phosphatases that dephosphorylate both phosphothreonine and phosphotyrosine residues on their substrate proteins. The determination of the apo-protein structure of Cdc25A revealed that this enzyme has a completely different fold compared to all other phosphatases crystallised to date. The conformation of the active site residues does not seem very suitable for catalysis in this unliganded structure. We have studied some structural features of the Cdc25A apo-structure and a modelled Cdc25A-ligand complex by molecular dynamics simulations. The simulations predict a conformational change in the peptide backbone of the complex, which is not observed in the apo-structure. This ligand-induced conformational change yields a structure that is similar to other protein tyrosine phosphataseligand complexes that have been crystallised. The change in conformation takes place in the position between a serine and a glutamic acid residue in the phosphate binding loop. We suggest that this type of conformational change is an important molecular switch in the catalytic process.z 2000 Federation of European Biochemical Societies.

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Q: a molecular dynamics program for free energy calculations and empirical valence bond simulations in biomolecular systems

Cited by 304 publications

References 51 publications

Improving the Efficiency of Protein–Ligand Binding Free-Energy Calculations by System Truncation

Improving the Efficiency of Protein–Ligand Binding Free-Energy Calculations by System Truncation

Computer Simulation of Primary Kinetic Isotope Effects in the Proposed Rate-limiting Step of the Glyoxalase I Catalyzed Reaction

Prediction of a ligand‐induced conformational change in the catalytic core of Cdc25A

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