Optimization of a molecular mechanics force field for type‐II polyoxometalates focussing on electrostatic interactions: A case study

Courcot, Blandine; Bridgeman, Adam J.

doi:10.1002/jcc.21752

Cited by 7 publications

(10 citation statements)

References 51 publications

(39 reference statements)

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“…Simulations were run using the MMFF94x force field to optimize the binding configuration by scoring spatial contacts and electrostatic interactions (22,23). With 100 configurations set as an upper limit for the docking, the populated list of configurations was searched for docking modes that placed these inhibitors within close proximity to the heme-bound oxygen in orientations consistent with azole inhibition.…”

Section: Methodsmentioning

confidence: 99%

Contribution of Clinically Derived Mutations in ERG11 to Azole Resistance in Candida albicans

Flowers

Colón

Whaley

et al. 2015

Antimicrob Agents Chemother

232

191

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bIn Candida albicans, the ERG11 gene encodes lanosterol demethylase, the target of the azole antifungals. Mutations in ERG11 that result in an amino acid substitution alter the abilities of the azoles to bind to and inhibit Erg11, resulting in resistance. Although ERG11 mutations have been observed in clinical isolates, the specific contributions of individual ERG11 mutations to azole resistance in C. albicans have not been widely explored. We sequenced ERG11 in 63 fluconazole (FLC)-resistant clinical isolates. Fifty-five isolates carried at least one mutation in ERG11, and we observed 26 distinct positions in which amino acid substitutions occurred. We mapped the 26 distinct variant positions in these alleles to four regions in the predicted structure for Erg11, including its predicted catalytic site, extended fungus-specific external loop, proximal surface, and proximal surface-toheme region. In total, 31 distinct ERG11 alleles were recovered, with 10 ERG11 alleles containing a single amino acid substitution. We then characterized 19 distinct ERG11 alleles by introducing them into the wild-type azole-susceptible C. albicans SC5314 strain and testing them for susceptibilities to FLC, itraconazole (ITC), and voriconazole (VRC). The strains that were homozygous for the single amino acid substitutions Y132F, K143R, F145L, S405F, D446E, G448E, F449V, G450E, and G464S had a >4-fold increase in FLC MIC. The strains that were homozygous for several double amino acid substitutions had decreased azole susceptibilities beyond those conferred by any single amino acid substitution. These findings indicate that mutations in ERG11 are prevalent among azole-resistant clinical isolates and that most mutations result in appreciable changes in FLC and VRC susceptibilities.

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Section: Methodsmentioning

confidence: 99%

Contribution of Clinically Derived Mutations in ERG11 to Azole Resistance in Candida albicans

Flowers

Colón

Whaley

et al. 2015

Antimicrob Agents Chemother

232

191

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“…[29][30][31][32][33] GAs have been successfully used in force field development, including fitting of dihedral angle 34,35 and van der Waals 17,25 parameters, atomic polarizabilities, 16 parametrization of coarse-grained 36 and reactive 37,38 force fields, and applied in numerous ad hoc force field parameter optimizations. [39][40][41][42][43] Interestingly, although the assignment of the fixed point charges is a critical part of many force fields, the application of GAs and other evolutionary/stochastic optimization techniques to the MEP pointcharge fitting has not been explored, to the best of our knowledge.…”

Section: Introductionmentioning

confidence: 99%

Genetic Algorithm Optimization of Point Charges in Force Field Development: Challenges and Insights

2015

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Evolutionary methods, such as genetic algorithms (GAs), provide powerful tools for optimization of the force field parameters, especially in the case of simultaneous fitting of the force field terms against extensive reference data. However, GA fitting of the nonbonded interaction parameters that includes point charges has not been explored in the literature, likely due to numerous difficulties with even a simpler problem of the least-squares fitting of the atomic point charges against a reference molecular electrostatic potential (MEP), which often demonstrates an unusually high variation of the fitted charges on buried atoms. Here, we examine the performance of the GA approach for the least-squares MEP point charge fitting, and show that the GA optimizations suffer from a magnified version of the classical buried atom effect, producing highly scattered yet correlated solutions. This effect can be understood in terms of the linearly independent, natural coordinates of the MEP fitting problem defined by the eigenvectors of the least-squares sum Hessian matrix, which are also equivalent to the eigenvectors of the covariance matrix evaluated for the scattered GA solutions. GAs quickly converge with respect to the high-curvature coordinates defined by the eigenvectors related to the leading terms of the multipole expansion, but have difficulty converging with respect to the low-curvature coordinates that mostly depend on the buried atom charges. The performance of the evolutionary techniques dramatically improves when the point charge optimization is performed using the Hessian or covariance matrix eigenvectors, an approach with a significant potential for the evolutionary optimization of the fixed-charge biomolecular force fields.

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“…(1) in Ref. 19). We have previously introduced a charge scaling factor (SF) to tune the atomic charges with CHARMM22 parameters.This is required especially when the 1,4-interactions SFs and buffering constants are used.…”

Section: Computational Strategies: Optimization Of the Mixed Force Fieldmentioning

confidence: 91%

“…The first step relies on a new optimization of the mixed force field of MMFF94x and POMFF based on the same computational strategy as the one developed previously. [19] As underlined by Hermans, "the self-consistency of the force field is an important issue:one cannot introduce new energy terms or modify already existing terms without adjusting others. [22] "The second challenge is to overcome the problem of force field transferability when combining the two existing force fields.This remark is particularly true for the nonbonded term and it requires special care.…”

Section: B Courcot and A J Bridgemanmentioning

confidence: 99%

“…This step has been validated for isolated type-II POMs that contain two unshared atoms in a cis-configuration. [19] This nonbonded term is important when considering polyanions interacting with their environment. Focussing in this study on counterions, our first challenge is to mix our optimized force field for POMs with a force field already optimized for organic molecules.…”

Section: B Courcot and A J Bridgemanmentioning

confidence: 99%

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Modeling the interactions between polyoxometalates and their environment

Courcot

Bridgeman

2011

J Comput Chem

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To develop a force field suitable both for polyoxometalates (POMs) and organic cations, the Merck molecular force field 94x (MMFF94x) has been selected to describe the counterions used in POMs synthesis and has been combined with our force field optimized for type-II POMs with electrostatic and Van der Waals interactions included in the potential. Nontransferability of force fields is well-known and, to overcome this limitation, a charge-scaling factor (SF) has been introduced and optimized to tune the POMs force field parameters and adapt them to MMFF94x. The mixed MMFF94x/POMFF-II force field has been optimized and tested on different clusters based on hepta-molybdate. To validate our mixed force field comparison of the results obtained after molecular mechanics (MM), geometry optimizations with density-functional (DFT) calculations have been performed on the smallest system of interest. This has enabled a study of the accuracy of different functionals, especially on the description of hydrogen bonding, to be made. Results are promising in terms of structural accuracy. MM geometry optimization can be used on small POM clusters, competing reasonably well with DFT. When quantum approaches increase considerably the computational cost because of the size of the system studied, MM can be used, with the small reservation that even if the charge SF introduced improves the performance of the force field, further optimizations of the nonbonded term and the model used for the atomic charges may be necessary in further studies.

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Optimization of a molecular mechanics force field for type‐II polyoxometalates focussing on electrostatic interactions: A case study

Cited by 7 publications

References 51 publications

Contribution of Clinically Derived Mutations in ERG11 to Azole Resistance in Candida albicans

Contribution of Clinically Derived Mutations in ERG11 to Azole Resistance in Candida albicans

Genetic Algorithm Optimization of Point Charges in Force Field Development: Challenges and Insights

Modeling the interactions between polyoxometalates and their environment

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