Accurate Determination of the Binding Free Energy for KcsA-Charybdotoxin Complex from the Potential of Mean Force Calculations with Restraints

Chen, Po-Chia; Kuyucak, Serdar

doi:10.1016/j.bpj.2011.03.052

Cited by 60 publications

(97 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The calculated binding free energies are seen to reproduce the experimental values within the chemical accuracy of 1 kcal/mol in all three cases. Using a similar methodology, we have previously reproduced the binding free energy for the KcsA*−charybdotoxin complex, 22 where the experimental structure of the complex is available. 20 Thus, the success of the present binding free energy calculations gives strong support for the accuracy of the Kv1.x−ShK complex models employed in these calculations.…”

Section: ■ Results and Discussionmentioning

confidence: 97%

“…The radius R in the factor πR 2 measures the average crosssectional area of the binding pocket as explored by the COM of ShK (the reaction coordinate), and it is determined from the transverse fluctuations of the COM of ShK in the binding pocket. It has been shown previously that allowing R to vary with z gives essentially the same answer, 22 …”

Section: ■ Methodsmentioning

confidence: 91%

See 1 more Smart Citation

Affinity and Selectivity of ShK Toxin for the Kv1 Potassium Channels from Free Energy Simulations

2012

Self Cite

View full text Add to dashboard Cite

The voltage-gated potassium channel Kv1.3 is an attractive target for treatment of autoimmune diseases. ShK toxin from sea anemone is one of the most potent blockers of Kv1.3, and therefore ShK and its analogues have been proposed as therapeutic leads for such diseases. Increasing the selectivity of the proposed leads for Kv1.3 over other Kv1 channels is a major issue in this endeavor. Here we study binding of ShK toxin to Kv1 channels using free energy simulation methods. Homology models for Kv1.1 and Kv1.3 channels are constructed using the crystal structure of Kv1.2. The initial poses for the Kv1.x-ShK complexes are obtained using HADDOCK, which are then refined via molecular dynamics simulations. The binding mode in each complex is characterized by identifying the strongly interacting residues, which compare well with available mutagenesis studies. For each complex, the potential of mean force is calculated from umbrella sampling simulations, and the corresponding absolute binding free energy is determined. The computed binding free energies are in good agreement with the experimental data, which increases the confidence on the model complexes. The insights gained on Kv1.x-ShK binding modes will be valuable in the development of new ShK analogues with better selectivity properties.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 97%

Section: ■ Methodsmentioning

confidence: 91%

Affinity and Selectivity of ShK Toxin for the Kv1 Potassium Channels from Free Energy Simulations

2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…MD was conducted for each window for 15 ns with a harmonic restraint ( k PR = 1000 kJ mol −1 nm −2 ) applied to chain B to fix the peptide along the reaction coordinate and then the PMF was constructed. The unbiased PMF was calculated using WHAM and the Δ G dissociation was evaluated as the difference in energy between the plateau and energy minimum along the PMF curve [68].…”

Section: Methodsmentioning

confidence: 99%

In Silico Insights into Protein-Protein Interactions and Folding Dynamics of the Saposin-Like Domain of Solanum tuberosum Aspartic Protease

2014

View full text Add to dashboard Cite

The plant-specific insert is an approximately 100-residue domain found exclusively within the C-terminal lobe of some plant aspartic proteases. Structurally, this domain is a member of the saposin-like protein family, and is involved in plant pathogen defense as well as vacuolar targeting of the parent protease molecule. Similar to other members of the saposin-like protein family, most notably saposins A and C, the recently resolved crystal structure of potato (Solanum tuberosum) plant-specific insert has been shown to exist in a substrate-bound open conformation in which the plant-specific insert oligomerizes to form homodimers. In addition to the open structure, a closed conformation also exists having the classic saposin fold of the saposin-like protein family as observed in the crystal structure of barley (Hordeum vulgare L.) plant-specific insert. In the present study, the mechanisms of tertiary and quaternary conformation changes of potato plant-specific insert were investigated in silico as a function of pH. Umbrella sampling and determination of the free energy change of dissociation of the plant-specific insert homodimer revealed that increasing the pH of the system to near physiological levels reduced the free energy barrier to dissociation. Furthermore, principal component analysis was used to characterize conformational changes at both acidic and neutral pH. The results indicated that the plant-specific insert may adopt a tertiary structure similar to the characteristic saposin fold and suggest a potential new structural motif among saposin-like proteins. To our knowledge, this acidified PSI structure presents the first example of an alternative saposin-fold motif for any member of the large and diverse SAPLIP family.

show abstract

“…The sampled coordinates of the ligand are unbiased and combined in an optimal way using the weighted histogram analysis method [54]. That the PMF method could yield an accurate binding free energy for a toxin peptide was first shown for binding of charybdotoxin to a KcsA potassium channel mimic [55]. This provided an important test case for the viability of the method because the structure of the complex was known [34], and there was no uncertainty in that regard.…”

Section: Methodsmentioning

confidence: 99%

Computational Approaches for Designing Potent and Selective Analogs of Peptide Toxins as Novel Therapeutics

Kuyucak

Norton

2014

Future Med. Chem.

Self Cite

View full text Add to dashboard Cite

Peptide toxins provide valuable therapeutic leads for many diseases. As they bind to their targets with high affinity, potency is usually ensured. However, toxins also bind to off-target receptors, causing potential side effects. Thus, a major challenge in generating drugs from peptide toxins is ensuring their specificity for their intended targets. Computational methods can play an important role in solving such design problems through construction of accurate models of receptor–toxin complexes and calculation of binding free energies. Here we review the computational methods used for this purpose and their application to toxins targeting ion channels. We describe ShK and HsTX1 toxins, high-affinity blockers of the voltage-gated potassium channel Kv1.3, which could be developed as therapeutic agents for autoimmune diseases.

show abstract

Accurate Determination of the Binding Free Energy for KcsA-Charybdotoxin Complex from the Potential of Mean Force Calculations with Restraints

Cited by 60 publications

References 31 publications

Affinity and Selectivity of ShK Toxin for the Kv1 Potassium Channels from Free Energy Simulations

Affinity and Selectivity of ShK Toxin for the Kv1 Potassium Channels from Free Energy Simulations

In Silico Insights into Protein-Protein Interactions and Folding Dynamics of the Saposin-Like Domain of Solanum tuberosum Aspartic Protease

Computational Approaches for Designing Potent and Selective Analogs of Peptide Toxins as Novel Therapeutics

Contact Info

Product

Resources

About