Electrostatic effects in proteins: comparison of dielectric and charge models

Mehler, Ernest L.; Solmajer, T.

doi:10.1093/protein/4.8.903

Cited by 287 publications

(189 citation statements)

References 6 publications

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“…The second term is a directional hydrogen bond based potential term (Goodford, 1985). Screened Coulomb potentials where a distance dependent dielectric constant is used to model solvent effects describe the third term (Mehler, 1991). The loss of conformational entropy due to binding is calculated in the fourth and fifth terms.…”

Section: Molecular Systems and Computational Methodsmentioning

confidence: 99%

Towards the Selective Inhibition of Glycolytic Pathway Enzymes: A Computational Analysis of Plasmodium falciparum and Human Triosephosphate Isomerase Ligand Interactions.

Alexandru

Forlemu

2016

IJURCA

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This work has undergone a double-blind review by a minimum of two faculty members from institutions of higher learning from around the world. The faculty reviewers have expertise in disciplines closely related to those represented by this work. If possible, the work was also reviewed by undergraduates in collaboration with the faculty reviewers. AbstractPlasmodium falciparum is main causative agent of malaria, a disease that affects half of world's population. The parasite's dependence on glycolysis makes this pathway a suitable target for drug development. Understanding the structure-function dynamics of glycolytic enzymes in different species has an important impact on the development of selective drug analogues. Parasitic resistance and drug side effects of current antimalarial drugs have complicated and increased the cost of curing malaria.Molecular docking was used to explore structural motifs responsible for the interactions between triose phosphate isomerase (TIM) from Plasmodium falciparum (PFTIM) and human (HTIM) tissues. Fourteen antimalarial drugs were examined. The binding affinities and domains identified serve as a basis for modeling novel analogues.For all drugs modeled, PFTIM complexes displayed stronger binding affinities compared to HTIM. A dissociation constant (K I ) of 40.2 mM was obtained for the interaction between primaquine and HTIM and 1.22 mM with PFTIM. This represents a 33-fold increase in selective binding to PFTM compared to HTIM. Mefloquine shows a 24-fold increase, and one new test ligand showed 25-fold increase in binding.The dimer interface and other pocket close to the active site are the main pockets observed by the docking studies. Key residues at the dimer interphase (Y48, D49, V46, S45, E65, S211) form a tight pocket with favorable polar contacts. 75% of PFTIM ligand complexes preferred the dimer interphase suggesting a potential site for non-competitive inhibition. These data suggest that TIM is a candidate for development of antimalarial drugs.

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Section: Molecular Systems and Computational Methodsmentioning

confidence: 99%

Towards the Selective Inhibition of Glycolytic Pathway Enzymes: A Computational Analysis of Plasmodium falciparum and Human Triosephosphate Isomerase Ligand Interactions.

Alexandru

Forlemu

2016

IJURCA

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“…Grid spacing was set to 0.375 Å, with 70 grid points centered on calcium ion 1. The electrostatic interaction energy grid used a sigmoidal distance-dependent dielectric function (22) to account for the solvent-screening effect. Self-consistent 12-6 Lennard-Jones coefficients (19) were used along with a distance criterion with sinusoidal directional attenuation to account for hydrogen bonding (21).…”

Section: Methodsmentioning

confidence: 99%

Polysaccharide Recognition by Surfactant Protein D: Novel Interactions of a C-Type Lectin with Nonterminal Glucosyl Residues

et al. 2001

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Surfactant protein D (SP-D), a C-type lectin, is an important pulmonary host defense molecule. Carbohydrate binding is critical to its host defense properties, but the precise polysaccharide structures recognized by the protein are unknown. SP-D binding toAspergillus fumigatus is strongly inhibited by a soluble β-(1→6)-linked but not by a soluble β-(1→3)-linked glucosyl homopolysaccharide (pustulan and laminarin, respectively), suggesting that SP-D recognizes only certain polysaccharide configurations, likely through differential binding to nonterminal glucosyl residues. In this study we have computationally docked α/β-dglucopyranose and α/β-(1→2)-, α/β-(1→3)-, α/β-(1→4)-, and α/β-(1→6)-linked glucosyl trisaccharides into the SP-D carbohydrate recognition domain. As with the mannose-binding proteins, we found significant hydrogen bonding between the protein and the vicinal, equatorial OH groups at the 3 and 4 positions on the sugar ring. Our docking studies predict that α/β-(1→2)-, α-(1→4)-, and α/β-(1→6)-linked but not α/β-(1→3)-linked glucosyl trisaccharides can be bound by their internal glucosyl residues and that binding also occurs through interactions of the protein with the 2-and 3-equatorial OH groups on the glucosyl ring. By using various soluble glucosyl homopolysaccharides as inhibitors of SP-D carbohydrate binding, we confirmed the interactions predicted by our modeling studies. Given the sequence and structural similarity between SP-D and other C-type lectins, many of the predicted interactions should be applicable to this protein family. Disciplines Biochemical and Biomolecular Engineering | Biological Engineering | Chemical Engineering CommentsThis work was supported by grants from NIH (HL-29891) and EPA (R825702 ABSTRACT: Surfactant protein D (SP-D), a C-type lectin, is an important pulmonary host defense molecule. Carbohydrate binding is critical to its host defense properties, but the precise polysaccharide structures recognized by the protein are unknown. SP-D binding to Aspergillus fumigatus is strongly inhibited by a soluble -(1f6)-linked but not by a soluble -(1f3)-linked glucosyl homopolysaccharide (pustulan and laminarin, respectively), suggesting that SP-D recognizes only certain polysaccharide configurations, likely through differential binding to nonterminal glucosyl residues. In this study we have computationally docked R/ -D-glucopyranose and R/ -(1f2)-, R/ -(1f3)-, R/ -(1f4)-, and R/ -(1f6)-linked glucosyl trisaccharides into the SP-D carbohydrate recognition domain. As with the mannose-binding proteins, we found significant hydrogen bonding between the protein and the vicinal, equatorial OH groups at the 3 and 4 positions on the sugar ring. Our docking studies predict that R/ -(1f2)-, R-(1f4)-, and R/ -(1f6)-linked but not R/ -(1f3)-linked glucosyl trisaccharides can be bound by their internal glucosyl residues and that binding also occurs through interactions of the protein with the 2-and 3-equatorial OH groups on the glucosyl ring. By using various soluble glucosyl homopo...

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“…Lennard-jones parameters 12-10 and 12-6 (supplied with the program package) were used for modeling H-bonds and van der Waals interactions, respectively. The distance-dependent dielectric permittivity of Mehler and Solmajer was used in the calculations of the electrostatic grid maps (26). The Lamarckian genetic algorithm (LGA) with the pseudo-Solis and Wets modification (LGA/pSW) method was used with default parameters except for the 0 maximum number of energy evaluations 0 which was increased to 1 million from …”

Section: Docking Simulationsmentioning

confidence: 99%

Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase

et al. 2009

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SummaryA structure-based approach has been adopted to develop 2 0 -substituted analogs of triclosan. The Cl at position 2 0 in ring B of triclosan was chemically substituted with other functional groups like NH 2 , NO 2 and their inhibitory potencies against PfENR were determined. The binding energies of the 2 0 substituted analogs of triclosan for enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum were determined using Autodock. Based on the autodock results, we synthesized the potential compounds. The IC 50 and inhibition constant (K i ) of 2 0 substituted analogs of triclosan were determined against purified PfENR. Among them, two compounds, 2-(2 0 -Amino-4 0 -chloro-phenoxy)-5-chloro-phenol (compound 4) and 5-chloro-2-(4 0 -chloro-2 0 -nitro-phenoxy)-phenol) (compound 5) exhibited good potencies. Compound 4 followed uncompetitive inhibition kinetics with crotonoyl CoA and competitive with NADH. It was shown to have an IC 50 of 110 nM; inhibition constant was 104 nM with the substrate and 61 nM with the cofactor. IC 50 of compound 5 was determined to be 229 nM. Compounds 4 and 5 showed significant inhibition of the parasite growth in P. falciparum culture.

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Electrostatic effects in proteins: comparison of dielectric and charge models

Cited by 287 publications

References 6 publications

Towards the Selective Inhibition of Glycolytic Pathway Enzymes: A Computational Analysis of Plasmodium falciparum and Human Triosephosphate Isomerase Ligand Interactions.

Towards the Selective Inhibition of Glycolytic Pathway Enzymes: A Computational Analysis of Plasmodium falciparum and Human Triosephosphate Isomerase Ligand Interactions.

Polysaccharide Recognition by Surfactant Protein D: Novel Interactions of a C-Type Lectin with Nonterminal Glucosyl Residues

Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase

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