View source for Physics:FoldX

'''FoldX''' is a [[Software:Molecular design software|protein design]] algorithm that uses an empirical [[Chemistry:Force field|force field]].  It can determine the energetic effect of point mutations as well as the [[Physics:Interaction energy|interaction energy]] of [[Biology:Protein|protein]] complexes (including Protein-[[Biology:DNA|DNA]]). FoldX can mutate protein and DNA side chains using a probability-based rotamer library, while exploring alternative conformations of the surrounding side chains.

== Applications ==
* Prediction of the effect of point mutations or human [[Biology:Single-nucleotide polymorphism|SNPs]] on protein stability or protein complexes
* Protein design to improve stability or modify affinity or specificity
* [[Biology:Homology modeling|Homology modeling]]

== The FoldX force field ==
The energy function includes terms that have been found to be important for protein stability, where the energy of [[Biology:Protein folding|unfolding]] (∆G) of a target protein is calculated using the equation:

∆G = ∆G<sub>vdw</sub> + ∆G<sub>solvH</sub> + ∆G<sub>solvP</sub> + ∆G<sub>hbond</sub> + ∆G<sub>wb</sub> + ∆G<sub>el</sub> + ∆S<sub>mc</sub> + ∆S<sub>sc</sub>
 
Where ∆G<sub>vdw</sub> is the sum of the [[Physics:Van der Waals force|Van der Waals]] contributions of all atoms with respect to the same interactions with the solvent. ∆G<sub>solvH</sub> and ∆G<sub>solvP</sub> is the difference in [[Chemistry:Solvation|solvation]] energy for apolar and polar groups, respectively, when going from the unfolded to the folded state. ∆Ghbond is the free energy difference between the formation of an intra-molecular [[Chemistry:Hydrogen bond|hydrogen-bond]] compared to inter-molecular [[Chemistry:Hydrogen bond|hydrogen-bond]] formation (with solvent). ∆G<sub>wb</sub> is the extra stabilizing free energy provided by a water molecule making more than one [[Chemistry:Hydrogen bond|hydrogen-bond]] to the protein (water bridges) that cannot be taken into account with non-explicit solvent approximations. ∆G<sub>el</sub> is the electrostatic contribution of charged groups, including the helix dipole.  ∆S<sub>mc</sub> is the [[Physics:Entropy|entropy]] cost for fixing the backbone in the folded state. This term is dependent on the intrinsic tendency of a particular [[Chemistry:Amino acid|amino acid]] to adopt certain dihedral angles. ∆S<sub>sc</sub> is the entropic cost of fixing a side chain in a particular conformation. The energy values of ∆G<sub>vdw</sub>, ∆G<sub>solvH</sub>, ∆G<sub>solvP</sub> and ∆G<sub>hbond</sub> attributed to each atom type have been derived from a set of experimental data, and ∆S<sub>mc</sub> and ∆S<sub>sc</sub> have been taken from theoretical estimates. The [[Physics:Van der Waals force|Van der Waals]] contributions are derived from vapor to water energy transfer, while in the protein we are going from solvent to protein.

For protein-protein interactions, or protein-DNA interactions  FoldX calculates ∆∆G of interaction :

∆∆G<sub>ab</sub> = ∆G<sub>ab</sub>- (∆G<sub>a</sub> + ∆G<sub>b</sub>) + ∆G<sub>kon</sub> + ∆S<sub>sc</sub>

∆G<sub>kon</sub> reflects the effect of electrostatic interactions on the k<sub>on</sub>. ∆S<sub>sc</sub> is the loss of translational and rotational entropy upon making the complex.

== Key features ==
* ''RepairPDB'': [[Chemistry:Energy minimization|energy minimization]] of a [[Biology:Protein structure|protein structure]]
* ''BuildModel'': in silico [[Biology:Site-directed mutagenesis|mutagenesis]] or homology modeling with predicted energy changes
* ''AnalyseComplex'': interaction energy calculation
* ''Stability'': prediction of free energy changes between alternative structures
* ''AlaScan'': in silico alanine scan of a protein structure with predicted energy changes
* ''SequenceDetail'': per residue free energy decomposition into separate energy terms (hydrogen bonding, Van der Waals energy, electrostatics, ...)

== Graphical interface ==
Native FoldX is run from the command line. A FoldX plugin for the YASARA molecular graphics program has been developed to access various FoldX tools inside a graphical environment. The results of e.g. in silico mutations or [[Biology:Homology modeling|homology modeling]] with FoldX can be directly analyzed on screen.

== Further reading ==
{{refbegin | 2}}
{{PBB_Further_reading 
| citations = 
*{{cite journal  |vauthors=Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L |title=The FoldX web server: an online force field. |journal=Nucleic Acids Res. |volume=33 |pages= W382-8 |year= 2005 |pmid= 15980494 |doi=10.1093/nar/gki387 |issue=Web Server issue |pmc=1160148}}
*{{cite journal  |vauthors=Schymkowitz J, Rousseau F, Martins IC, Ferkinghoff-Borg J, Stricher F, Serrano L |title=Prediction of water and metal binding sites and their affinities by using the Fold-X force field. |journal=Proc Natl Acad Sci USA |volume=102 |pages= 10147–52 |year= 2005 |pmid= 16006526 |doi=10.1073/pnas.0501980102 |issue=29 |pmc=1177371}}
*{{cite journal  |vauthors=Guerois R, Nielsen JE, Serrano L |title=Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. |journal=J Mol Biol |volume=320 |pages= 369–87 |year= 2002 |pmid= 12079393 |doi=10.1016/S0022-2836(02)00442-4 |issue=2}}
}}
{{refend}}

==External links==
* [http://foldx.crg.es http://foldx.crg.es] FoldX website
* [http://foldxyasara.switchlab.org http://foldxyasara.switchlab.org] FoldX plugin for YASARA

[[Category:Bioinformatics]]
[[Category:Bioinformatics software]]
[[Category:Molecular modelling]]
[[Category:Molecular modelling software]]
[[Category:Protein structure]]

{{Sourceattribution|FoldX|1}}