FoldX
Encyclopedia
FoldX is a protein design
algorithm that uses an empirical force field
. It can determine the energetic effect of point mutations as well as the interaction energy
of protein
complexes (including Protein-DNA
). FoldX can mutate protein and DNA side chains using a probability-based rotamer library, while exploring alternative conformations of the surrounding side chains.
(∆G) of a target protein is calculated using the equation:
∆G = ∆Gvdw + ∆GsolvH + ∆GsolvP + ∆Ghbond + ∆Gwb + ∆Gel + ∆Smc + ∆Ssc
Where ∆Gvdw is the sum of the Van der Waals
contributions of all atoms with respect to the same interactions with the solvent. ∆GsolvH and ∆GsolvP is the difference in 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 hydrogen-bond
compared to inter-molecular hydrogen-bond
formation (with solvent). ∆Gwb is the extra stabilizing free energy provided by a water molecule making more than one hydrogen-bond
to the protein (water bridges) that cannot be taken into account with non-explicit solvent approximations. ∆Gel is the electrostatic contribution of charged groups, including the helix
dipole. ∆Smc is the entropy
cost for fixing the backbone in the folded state. This term is dependent on the intrinsic tendency of a particular amino acid
to adopt certain dihedral angles. ∆Ssc is the entropic cost of fixing a side chain in a particular conformation. The energy values of ∆Gvdw, ∆GsolvH, ∆GsolvP and ∆Ghbond attributed to each atom type have been derived from a set of experimental data, and ∆Smc and ∆Smc have been taken from theoretical estimates. The 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 :
∆∆Gab = ∆Gab- (∆Ga + ∆Gb) + ∆Gkon + ∆Ssc
∆Gkon reflects the effect of electrostatic interactions on the kon. ∆Ssc is the loss of translational and rotational entropy upon making the complex.
molecular graphics program has been developed to access various FoldX tools inside a graphical environment. The results of e.g. in silico mutations or homology modeling
with FoldX can be directly analyzed on screen.
Molecular Design software
Molecular design software is software for molecular modeling, that provides special support for developing molecular models de novo.In contrast to the usual molecular modeling programs such as the molecular dynamics and quantum chemistry programs, such software directly supports the aspects related...
algorithm that uses an empirical force field
Force field (chemistry)
In the context of molecular modeling, a force field refers to the form and parameters of mathematical functions used to describe the potential energy of a system of particles . Force field functions and parameter sets are derived from both experimental work and high-level quantum mechanical...
. It can determine the energetic effect of point mutations as well as the interaction energy
Interaction energy
In physics, interaction energy is the contribution to the total energy that is caused by an interaction between the objects being considered.The interaction energy usually depends on the relative position of the objects...
of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
complexes (including Protein-DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
). 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 SNPs on protein stability or protein complexes
- Protein design to improve stability or modify affinity or specificity
- Homology modelingHomology modelingHomology modeling, also known as comparative modeling of protein refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein...
The FoldX force field
The energy function includes terms that have been found to be important for protein stability, where the energy of unfoldingProtein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
(∆G) of a target protein is calculated using the equation:
∆G = ∆Gvdw + ∆GsolvH + ∆GsolvP + ∆Ghbond + ∆Gwb + ∆Gel + ∆Smc + ∆Ssc
Where ∆Gvdw is the sum of the Van der Waals
Van der Waals force
In physical chemistry, the van der Waals force , named after Dutch scientist Johannes Diderik van der Waals, is the sum of the attractive or repulsive forces between molecules other than those due to covalent bonds or to the electrostatic interaction of ions with one another or with neutral...
contributions of all atoms with respect to the same interactions with the solvent. ∆GsolvH and ∆GsolvP is the difference in solvation
Solvation
Solvation, also sometimes called dissolution, is the process of attraction and association of molecules of a solvent with molecules or ions of a solute...
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 hydrogen-bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
compared to inter-molecular hydrogen-bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
formation (with solvent). ∆Gwb is the extra stabilizing free energy provided by a water molecule making more than one hydrogen-bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
to the protein (water bridges) that cannot be taken into account with non-explicit solvent approximations. ∆Gel is the electrostatic contribution of charged groups, including the helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
dipole. ∆Smc is the entropy
Entropy
Entropy is a thermodynamic property that can be used to determine the energy available for useful work in a thermodynamic process, such as in energy conversion devices, engines, or machines. Such devices can only be driven by convertible energy, and have a theoretical maximum efficiency when...
cost for fixing the backbone in the folded state. This term is dependent on the intrinsic tendency of a particular amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
to adopt certain dihedral angles. ∆Ssc is the entropic cost of fixing a side chain in a particular conformation. The energy values of ∆Gvdw, ∆GsolvH, ∆GsolvP and ∆Ghbond attributed to each atom type have been derived from a set of experimental data, and ∆Smc and ∆Smc have been taken from theoretical estimates. The Van der Waals
Van der Waals force
In physical chemistry, the van der Waals force , named after Dutch scientist Johannes Diderik van der Waals, is the sum of the attractive or repulsive forces between molecules other than those due to covalent bonds or to the electrostatic interaction of ions with one another or with neutral...
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 :
∆∆Gab = ∆Gab- (∆Ga + ∆Gb) + ∆Gkon + ∆Ssc
∆Gkon reflects the effect of electrostatic interactions on the kon. ∆Ssc is the loss of translational and rotational entropy upon making the complex.
Key features
- RepairPDB: energy minimization of a protein structure
- BuildModel: in silico 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 YASARAYasara
YASARA, Yet Another Scientific Artificial Reality Application, is a molecular visualisation, modelling, and dynamics program that can be used for a series of scientific applications as is expressed by the large number of mentioning this software. The free version of YASARA is well suited for...
molecular graphics program has been developed to access various FoldX tools inside a graphical environment. The results of e.g. in silico mutations or homology modeling
Homology modeling
Homology modeling, also known as comparative modeling of protein refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein...
with FoldX can be directly analyzed on screen.
Links
- http://foldx.crg.es FoldX website
- http://foldxyasara.switchlab.org FoldX plugin for YASARA