Computational Determination of the Relative Free Energy of Binding – Application to Alanine Scanning Mutagenesis

Moreira, Irina S.; Fernandes, Pedro A.; Ramos, María J.

doi:10.1007/1-4020-5372-x_6

Cited by 8 publications

(7 citation statements)

References 276 publications

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“…The most rapid methods for estimation of binding free energies are the empirical or knowledge‐based (statistical) scoring approaches in conjunction with simple physical models 113. More time consuming methods involve fully atomistic simulations and include both the rigorous free energy perturbation114 and thermodynamic integration,115 and more approximate methods such as MM‐PBSA 116.…”

Section: Hot Spotsmentioning

confidence: 99%

Hot spots—A review of the protein–protein interface determinant amino‐acid residues

2007

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Proteins tendency to bind to one another in a highly specific manner forming stable complexes is fundamental to all biological processes. A better understanding of complex formation has many practical applications, which include the rational design of new therapeutic agents, and the analysis of metabolic and signal transduction networks. Alanine-scanning mutagenesis made possible the detection of the functional epitopes, and demonstrated that most of the protein-protein binding energy is related only to a group of few amino acids at intermolecular protein interfaces: the hot spots. The scope of this review is to summarize all the available information regarding hot spots for a better atomic understanding of their structure and function. The ultimate objective is to improve the rational design of complexes of high affinity and specificity as well as that of small molecules, which can mimic the functional epitopes of the proteic complexes.

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Section: Hot Spotsmentioning

confidence: 99%

Hot spots—A review of the protein–protein interface determinant amino‐acid residues

2007

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“…The simulations are carried out in an effective dielectric medium using a distance-dependent dielectric constant as done in previous works. − In this way, the presence of added salts cannot be considered, and specific hydration effects are neglected, but this approximation allows probing lengthy large-scale surface rearrangements thanks both to the smaller system size and to the much faster relaxation rate due to the lack of friction with the solvent molecules. We already proposed two arguments to support this approach, based on one hand on a comparison with simulations in explicit water (the changes in the solvation energy was estimated to amount to about 10%) and on the other hand on the simulations of molecular recognition phenomena in supramolecular host–guest complexes (exactly the same geometry was obtained at room temperature both with explicit water and with the effective dielectric medium) .…”

Section: Introductionmentioning

confidence: 99%

Surface Topography Effects in Protein Adsorption on Nanostructured Carbon Allotropes

Raffaini

Ganazzoli

2013

Langmuir

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We report a molecular dynamics (MD) simulation study of protein adsorption on the surface of nanosized carbon allotropes, namely single-walled carbon nanotubes (SWNT) considering both the convex outer surface and the concave inner surface, together with a graphene sheet for comparison. These systems are chosen to investigate the effect of the surface curvature on protein adsorption at the same surface chemistry, given by sp(2) carbon atoms in all cases. The simulations show that proteins do favorably interact with these hydrophobic surfaces, as previously found on graphite which has the same chemical nature. However, the main finding of the present study is that the adsorption strength does depend on the surface topography: in particular, it is slightly weaker on the outer convex surfaces of SWNT and is conversely enhanced on the inner concave SWNT surface, being therefore intermediate for flat graphene. We additionally find that oligopeptides may enter the cavity of common SWNT, provided their size is small enough and the tube diameter is large enough for both entropic and energetic reasons. Therefore, we suggest that proteins can effectively be used to solubilize in water single-walled (and by analogy also multiwalled) carbon nanotubes through adsorption on the outer surface, as indeed experimentally found, and to functionalize them after insertion of oligopeptides within the cavity of nanotubes of appropriate size.

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“…In the work presented here, we began with a computational alanine-scanning mutagenesis study, which has been shown to result in an overall 80% success rate of reproducing the correspondent experimental alanine-scanning mutagenesis data, as well as an 80% success rate of detecting the warm and hot spots in the protein−protein interface. − Subsequently, we performed a study of the importance of the solvent around energetically important amino acid residues. Finally, with the calculation of the radial distribution function and residence times of the water molecules near the hot/warm spots, we tried to rationalize the importance of the accessibility or inaccessibility to the solvent of the warm and hot spots.…”

Section: Introductionmentioning

confidence: 99%

Hot Spot Occlusion from Bulk Water: a Comprehensive Study of the Complex between the Lysozyme HEL and the Antibody FVD1.3

2007

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Alanine scanning of protein-protein interfaces has shown that there are some residues in the protein-protein interfaces, responsible for most of the binding free energy, which are called hot spots. Hot spots tend to exist in densely packed central clusters, and a hypothesis has been proposed that considers that inaccessibility to the solvent must be a necessary condition to define a residue as a binding hot spot. This O-ring hypothesis is mainly based on the analysis of the accessible surface area (ASA) of 23 static, crystallographic structures of protein complexes. It is known, however, that protein flexibility allows for temporary exposures of buried interfacial groups, and even though the ASA provides a general trend of the propensity for hydration, protein/solvent-specific interactions or hydrogen bonding cannot be considered here. Therefore, a microscopic level, atomistic picture of hot spot solvation is needed to support the O-ring hypothesis. In this study, we began by applying a computational alanine-scanning mutagenesis technique, which reproduces the experimental results and allows for decomposing the binding free energy difference in its different energetic factors. Subsequently, we calculated the radial distribution function and residence times of the water molecules near the hot/warm spots to study the importance of the water environment around those energetically important amino acid residues. This study shows that within a flexible, dynamic protein framework, the warm/hot spot residues are, indeed, kept sheltered from the bulk solvent during the whole simulation, which allows a better interacting microenvironment.

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Computational Determination of the Relative Free Energy of Binding – Application to Alanine Scanning Mutagenesis

Cited by 8 publications

References 276 publications

Hot spots—A review of the protein–protein interface determinant amino‐acid residues

Hot spots—A review of the protein–protein interface determinant amino‐acid residues

Surface Topography Effects in Protein Adsorption on Nanostructured Carbon Allotropes

Hot Spot Occlusion from Bulk Water: a Comprehensive Study of the Complex between the Lysozyme HEL and the Antibody FVD1.3

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