Are Current Semiempirical Methods Better Than Force Fields? A Study from the Thermodynamics Perspective

Seabra, Gustavo; Walker, Ross C.; Roitberg, Adrián E.

doi:10.1021/jp903474v

Cited by 51 publications

(18 citation statements)

References 108 publications

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“…32–34 The performance of the ff99SB force field has been shown to satisfactorily model hydrogen bonding, outperforming most semi-empirical QM/MM methods in reproducing some experimental properties such as NMR dipolar coupling constants. 35–37 …”

Section: Methodsmentioning

confidence: 99%

Role of Active Site Residues in Promoting Cobalt–Carbon Bond Homolysis in Adenosylcobalamin-Dependent Mutases Revealed through Experiment and Computation

et al. 2013

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Adenosylcobalamin serves as a source of reactive free radicals that are generated by homolytic scission of the coenzyme’s cobalt-carbon bond. AdoCbl-dependent enzymes accelerate AdoCbl homolysis by ~1012-fold, but the mechanism by which this is accomplished remains unclear. We have combined experimental and computational approaches to gain molecular-level insight into this process for glutamate mutase. Two residues, glutamate-330 and lysine-326, form hydrogen bonds with the adenosyl group of the coenzyme. A series of mutations were introduced at these positions that impair the enzyme’s ability to catalyze coenzyme homolysis and tritium exchange with the substrate by 2 – 4 orders of magnitude. These mutations, together with the wild-type enzyme, were also characterized in silico by molecular dynamics simulations of the enzyme:AdoCbl:substrate with AdoCbl modeled in either the associated (Co-C bond formed) or the dissociated (adenosyl radical + CblII) state. The simulations reveal that the number of hydrogen bonds between the adenosyl group and the protein side-chains increases in the homolytically-dissociated state, with respect to the associated state, for both the wild-type and mutant enzymes. The mutations also cause a progressive increase in the mean distance between the 5′-carbon of the adenosyl radical and the abstractable hydrogen of the substrate. Interestingly, the distance between the 5′-carbon and substrate hydrogen, determined computationally, was found to inversely correlate with the logk for tritium exchange (r = 0.93) determined experimentally. Taken together, these results point to a dual role for these residues: they both stabilize the homolytic state through electrostatic interactions between the protein and the dissociated coenzyme, and correctly position the adenosyl radical to facilitate hydrogen abstraction from the substrate.

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Section: Methodsmentioning

confidence: 99%

Role of Active Site Residues in Promoting Cobalt–Carbon Bond Homolysis in Adenosylcobalamin-Dependent Mutases Revealed through Experiment and Computation

et al. 2013

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“…Furthermore, scalar couplings calculated by a Karplus relation are sensitive to which empirical Karplus parameters are used 11a, 11b . It also has been suggested that helical structures are not stable enough in ff99SB 11b, 11c, 14 .…”

Section: Introductionmentioning

confidence: 99%

ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB

Maier

Martinez

Kasavajhala

et al. 2015

J. Chem. Theory Comput.

8,360

7,144

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Molecular mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Average errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a physically motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but improved secondary structure content in small peptides, and reproduction of NMR χ1 scalar coupling measurements for proteins in solution. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements.

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“…At the first stage, a molecular-mechanical minimization was performed to remove the largest strains in the system. At the second stage, the semi-empirical Hamiltonian RM1, whose efficiency was demonstrated in simulations of biomolecules [49, 50], was used to describe the interactions between the substrate and the catalytic residues His263 and His493 more precisely. The most important interatomic distances in the active site of the starting and optimized Tdp1 models are listed in Table 1 .…”

Section: Resultsmentioning

confidence: 99%

Structure Modeling of Human TyrosylDNA Phosphodiesterase 1 and Screening for Its Inhibitors

et al. 2017

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The DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) represents a potential molecular target for anticancer therapy. A human Tdp1 model has been constructed using the methods of quantum and molecular mechanics, taking into account the ionization states of the amino acid residues in the active site and their interactions with the substrate and competitive inhibitors. The oligonucleotide- and phosphotyrosine-binding cavities important for the inhibitor design have been identified in the enzyme’s active site. The developed molecular model allowed us to uncover new Tdp1 inhibitors whose sulfo group is capable of occupying the position of the 3’-phosphate group of the substrate and forming hydrogen bonds with Lys265, Lys495, and other amino acid residues in the phosphotyrosine binding site.

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Are Current Semiempirical Methods Better Than Force Fields? A Study from the Thermodynamics Perspective

Cited by 51 publications

References 108 publications

Role of Active Site Residues in Promoting Cobalt–Carbon Bond Homolysis in Adenosylcobalamin-Dependent Mutases Revealed through Experiment and Computation

Role of Active Site Residues in Promoting Cobalt–Carbon Bond Homolysis in Adenosylcobalamin-Dependent Mutases Revealed through Experiment and Computation

ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB

Structure Modeling of Human TyrosylDNA Phosphodiesterase 1 and Screening for Its Inhibitors

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