Microscopic and semimicroscopic calculations of electrostatic energies in proteins by the POLARIS and ENZYMIX programs

Lee, Frederick S.; Chu, Zhen T.; Warshel, Arieh

doi:10.1002/jcc.540140205

Cited by 464 publications

(817 citation statements)

References 73 publications

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“…The starting point for our calculations was the high--resolution (1.6 Å) X--ray structure of MAO B in complex with 2--(2--benzofuranyl)--2--imidazoline), 13 pK a calculations were performed using the semi--macroscopic protein dipole / Langevin dipole approach of Warshel and coworkers, in its linear response approximation version (PDLD/S--LRA), 49,[54][55][56] To parameterize the charge distribution of oxidized FAD and dopamine, electrostatic potential derived atomic charges were obtained on the optimized structures at the (PCM)/B3LYP/6-31G(d) level of theory in conjunction with the UFF radii as implemented in Gaussian09 program. 57 The essence of the PDLD/LRA pK a calculation is to convert the problem of evaluating a pK a in a protein to evaluation of the change in "solvation" energy associated with moving the charge from water to the protein.…”

Section: Methodsmentioning

confidence: 99%

Computational Study of the pK_aValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Borštnar

Repič

Kamerlin

et al. 2012

J. Chem. Theory Comput.

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Monoamine oxidase (MAO), which exists in two isozymic forms, MAO A and MAO B, is an important flavoenzyme responsible for the metabolism of amine neurotransmitters such as dopamine, serotonin and norepinephrine. Despite extensive research effort, neither the catalytic nor the inhibition mechanisms of MAO have been completely understood. There has also been dispute with regard to the protonation state of the substrate upon entering the active site, as well as the identity of residues that are important for the initial deprotonation of irreversible acetylenic inhibitors, in accordance with the recently proposed mechanism. Therefore, in order to investigate features essential for the modes of action of MAO, we have calculated pK a values of three relevant tyrosine residues in the MAO B active site, with and without dopamine bound as the substrate (as well as the pK a of the dopamine itself in the active site). The calculated pK a values for Tyr188, Tyr398 and Tyr435 in the complex are found to be shifted upwards to 13.0, 13.7 and 14.7, respectively, relative to 10.1 in aqueous solution, ruling out the likelihood that they are viable proton acceptors. The altered tyrosine pK a values could be rationalized as an interplay of two opposing effects: insertion of positively charged bulky dopamine that lowers tyrosine pK a values, and subsequent removal of water molecules from the active site that elevates tyrosine pK a values, in which the latter prevails. Additionally, the pK a value of the bound dopamine (8.8) is practically unchanged compared to the corresponding value in aqueous solution (8.9), as would be expected from a charged amine placed in a hydrophobic active site consisting of aromatic moieties. We also observed potentially favorable cation-π interactions between -NH 3 + group on dopamine and aromatic moieties, which provide stabilizing effect to the charged fragment. Thus, we offer here theoretical evidence that the amine is most likely to be present in the active site in its protonated form, which is similar to the conclusion from experimental studies of MAO A (Jones et al. J. Neural Trans. 2007, 114, 707-712). However, the free energy cost of 3 transferring the proton from the substrate to the bulk solvent is only 1.9 kcal mol -1 , leaving open the possibility that the amine enters the chemical step in its neutral form. In conjunction with additional experimental and computational work, the data presented here should lead towards a deeper understanding of mechanisms of the catalytic activity and irreversible inhibition of MAO B, which can allow for the design of novel and improved MAO B inhibitors.

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Section: Methodsmentioning

confidence: 99%

Computational Study of the pK_aValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Borštnar

Repič

Kamerlin

et al. 2012

J. Chem. Theory Comput.

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“…All simulations were performed using the MOLARIS simulation package. 50 The nucleic acid bases were represented by AMBER charges 51 and ENZYMIX vdW parameters (after validation that these parameters give reliable solvation energies and base-pairing energies and structures). A single center model with the vdW parameters r* = 1.30 and ε = 0.06 kcal/mol 13 was used for the Mg 2+ ions.…”

Section: Methodsmentioning

confidence: 99%

Exploring the role of large conformational changes in the fidelity of DNA polymerase β

et al. 2007

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The relationships between the conformational landscape, nucleotide insertion catalysis and fidelity of DNA polymerase β are explored by means of computational simulations. The simulations indicate that the transition states for incorporation of right (R) and wrong (W) nucleotides reside in substantially different protein conformations. The protein conformational changes that reproduce the experimentally observed fidelity are significantly larger than the small rearrangements that usually accompany motions from the reactant state to the transition state in common enzymatic reactions. Once substrate binding has occurred, different constraints imposed on the transition states for insertion of R and W nucleotides render it highly unlikely that both transition states can occur in the same closed structure, because the predicted fidelity would then be many orders of magnitude too large. Since the conformational changes reduce the transition state energy of W incorporation drastically they decrease fidelity rather than increase it. Overall, a better agreement with experimental data is attained when the R is incorporated through a transition state in a closed conformation and W is incorporated through a transition state in one or perhaps several partially open conformations. The generation of free energy surfaces for R and W also allow us to analyze proposals about the relationship between induced fit and fidelity.

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“…The corresponding binding energies are obtained by following the same strategy used in our recent study, where we reproduced the observed change in TS binding free energy in different mutants and upon changing the base (Rucker et al 2009). In this approach, we evaluated the binding energy of the chemical (triphosphate) and the base sites separately, by running independent Protein Dipole/Langevin Dipole simulations (PDLD/S) using the LRA version (Lee et al 1993 ;Sham et al 2000), and using dielectric constants of 40 and 2 for the chemical (triphosphate) and base sites, respectively (the justification for this approach is presented in Rucker et al 2009). The corresponding calculated binding free energies reproduced the balance between the binding of the base and the chemical sites, which is the essence of the allosteric effect that controls the fidelity of DNA polymerases.…”

Section: Exploring the Molecular Basis For The Observed Fidelitymentioning

confidence: 99%

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

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333

448

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Phosphoryl transfer plays key roles in signaling, energy transduction, protein synthesis, and maintaining the integrity of the genetic material. On the surface, it would appear to be a simple nucleophile displacement reaction. However, this simplicity is deceptive, as, even in aqueous solution, the low-lying d-orbitals on the phosphorus atom allow for eight distinct mechanistic possibilities, before even introducing the complexities of the enzyme catalyzed reactions. To further complicate matters, while powerful, traditional experimental techniques such as the use of linear free-energy relationships (LFER) or measuring isotope effects cannot make unique distinctions between different potential mechanisms. A quarter of a century has passed since Westheimer wrote his seminal review, ‘Why Nature Chose Phosphate’ (Science 235 (1987), 1173), and a lot has changed in the field since then. The present review revisits this biologically crucial issue, exploring both relevant enzymatic systems as well as the corresponding chemistry in aqueous solution, and demonstrating that the only way key questions in this field are likely to be resolved is through careful theoretical studies (which of course should be able to reproduce all relevant experimental data). Finally, we demonstrate that the reason that naturereallychose phosphate is due to interplay between two counteracting effects: on the one hand, phosphates are negatively charged and the resulting charge-charge repulsion with the attacking nucleophile contributes to the very high barrier for hydrolysis, making phosphate esters among the most inert compounds known. However, biology is not only about reducing the barrier to unfavorable chemical reactions. That is, the same charge-charge repulsion that makes phosphate ester hydrolysis so unfavorable also makes it possible to regulate, by exploiting the electrostatics. This means that phosphate ester hydrolysis can not only be turned on, but also be turned off, by fine tuning the electrostatic environment and the present review demonstrates numerous examples where this is the case. Without this capacity for regulation, it would be impossible to have for instance a signaling or metabolic cascade, where the action of each participant is determined by the fine-tuned activity of the previous piece in the production line. This makes phosphate esters the ideal compounds to facilitate life as we know it.

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Microscopic and semimicroscopic calculations of electrostatic energies in proteins by the POLARIS and ENZYMIX programs

Cited by 464 publications

References 73 publications

Computational Study of the pK_aValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Computational Study of the pK_aValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Exploring the role of large conformational changes in the fidelity of DNA polymerase β

Why nature really chose phosphate

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Microscopic and semimicroscopic calculations of electrostatic energies in proteins by the POLARIS and ENZYMIX programs

Cited by 464 publications

References 73 publications

Computational Study of the pKaValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Computational Study of the pKaValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Exploring the role of large conformational changes in the fidelity of DNA polymerase β

Why nature really chose phosphate

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Computational Study of the pK_aValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Computational Study of the pK_aValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B