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Examining the assumptions underlying continuum-solvent models.

ABSTRACT: Continuum-solvent models (CSMs) have successfully predicted many quantities, including the solvation-free energies (?G) of small molecules, but they have not consistently succeeded at reproducing experimental binding free energies (??G), especially for protein-protein complexes. Several CSMs break ?G into the free energy (?Gvdw) of inserting an uncharged molecule into solution and the free energy (?Gel) gained from charging. Some further divide ?Gvdw into the free energy (?Grep) of inserting a nearly hard cavity into solution and the free energy (?Gatt) gained from turning on dispersive interactions between the solute and solvent. We show that for 9 protein-protein complexes neither ?Grep nor ?Gvdw was linear in the solvent-accessible area A, as assumed in many CSMs, and the corresponding components of ??G were not linear in changes in A. We show that linear response theory (LRT) yielded good estimates of ?Gatt and ??Gatt, but estimates of ??Gatt obtained from either the initial or final configurations of the solvent were not consistent with those from LRT. The LRT estimates of ?Gel differed by more than 100 kcal/mol from the explicit solvent model's (ESM's) predictions, and its estimates of the corresponding component (??Gel) of ??G differed by more than 10 kcal/mol. Finally, the Poisson-Boltzmann equation produced estimates of ?Gel that were correlated with those from the ESM, but its estimates of ??Gel were much less so. These findings may help explain why many CSMs have not been consistently successful at predicting ??G for many complexes, including protein-protein complexes.

SUBMITTER: Harris RC

PROVIDER: S-EPMC5340276 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Examining the assumptions underlying continuum-solvent models.

Harris Robert C RC Pettitt B Montgomery BM

Journal of chemical theory and computation 20150911 10

Continuum-solvent models (CSMs) have successfully predicted many quantities, including the solvation-free energies (ΔG) of small molecules, but they have not consistently succeeded at reproducing experimental binding free energies (ΔΔG), especially for protein-protein complexes. Several CSMs break ΔG into the free energy (ΔGvdw) of inserting an uncharged molecule into solution and the free energy (ΔGel) gained from charging. Some further divide ΔGvdw into the free energy (ΔGrep) of inserting a n ...[more]

PMID: 26574250

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Project description:BackgroundThe genomes of bacteria and archaea evolve by extensive loss and gain of genes which, for any group of related prokaryotic genomes, result in the formation of a pangenome with the universal, asymmetrical U-shaped distribution of gene commonality. However, the evolutionary factors that define the specific shape of this distribution are not thoroughly understood.ResultsWe investigate the fit of simple models of genome evolution to the empirically observed gene commonality distributions and genome intersections for 33 groups of closely related bacterial genomes. A model with an infinite external gene pool available for gene acquisition and constant genome size (IGP-CGS model), and two gene turnover rates, one for slow- and the other one for fast-evolving genes, allows two approaches to estimate the parameters for gene content dynamics. One is by fitting the model prediction to the distribution of the number of genes shared by precisely k genomes (gene commonality distribution) and another by analyzing the distribution of the number of genes common for k genome sets (k-cores). Both approaches produce a comparable overall quality of fit, although the former significantly overestimates the number of the universally conserved genes, while the latter overestimates the number of singletons. We further explore the effect of dropping each of the assumptions of the IGP-CGS model on the fit to the gene commonality distributions and show that models with either a finite gene pool or unequal rates of gene loss and gain (greater gene loss rate) eliminate the overestimate of the number of singletons or the core genome size.ConclusionsWe examine the assumptions that are usually adopted for modeling the evolution of the U-shaped gene commonality distributions in prokaryote genomes, namely, those of infinitely many genes and constant genome size. The combined analysis of genome intersections and gene commonality suggests that at least one of these assumptions is invalid. The violation of both these assumptions reflects the limited ability of prokaryotes to gain new genes. This limitation seems to stem, at least partly, from the horizontal gene transfer barrier, i.e., the cost of accommodation of foreign genes by prokaryotes. Further development of models taking into account the complexity of microbial evolution is necessary for an improved understanding of the evolution of prokaryotes.

Project description:Alamethicin is a 20-amino acid antibiotic peptide that forms voltage-gated ion channels in lipid bilayers. Here we report calculations of its association free energy with membranes. The calculations take into account the various free-energy terms that contribute to the transfer of the peptide from the aqueous phase into bilayers of different widths. The electrostatic and nonpolar contributions to the solvation free energy are calculated using continuum solvent models. The contributions from the lipid perturbation and membrane deformation effects and the entropy loss associated with peptide immobilization in the bilayer are estimated from a statistical thermodynamic model. The calculations were carried out using two classes of experimentally observed conformations, both of which are helical: the NMR and the x-ray crystal structures. Our calculations show that alamethicin is unlikely to partition into bilayers in any of the NMR conformations because they have uncompensated backbone hydrogen bonds and their association with the membrane involves a large electrostatic solvation free energy penalty. In contrast, the x-ray conformations provide enough backbone hydrogen bonds for the peptide to associate with bilayers. We tested numerous transmembrane and surface orientations of the peptide in bilayers, and our calculations indicate that the most favorable orientation is transmembrane, where the peptide protrudes approximately 4 A into the water-membrane interface, in very good agreement with electron paramagnetic resonance and oriented circular dichroism measurements. The calculations were carried out using two alamethicin isoforms: one with glutamine and the other with glutamate in the 18th position. The calculations indicate that the two isoforms have similar membrane orientations and that their insertion into the membrane is likely to involve a 2-A deformation of the bilayer, again, in good agreement with experimental data. The implications of the results for the biological function of alamethicin and its capacity to oligomerize and form ion channels are discussed.

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Examining the assumptions underlying continuum-solvent models.

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Examining the assumptions underlying continuum-solvent models.

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