FoldX is a

protein design Protein design is the rational design of new protein molecules to design novel activity, behavior, or purpose, and to advance basic understanding of protein function. Proteins can be designed from scratch (''de novo'' design) or by making calcula ...

algorithm that uses an empirical force field. It can determine the energetic effect of point

mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

as well as the

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. For example, Q_1 Q_2 / ( ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

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.

Applications

* Prediction of the effect of point mutations or human

SNPs In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...

on protein stability or protein complexes * Protein design to improve stability or modify affinity or specificity *

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 pr ...

The FoldX force field

The energy function includes terms that have been found to be important for protein stability, where the energy of unfolding (∆G) of a target protein is calculated using the equation: ∆G = ∆G_vdw + ∆G_solvH + ∆G_solvP + ∆G_hbond + ∆G_wb + ∆G_el + ∆S_mc + ∆S_sc Where ∆G_vdw is the sum of the Van der Waals contributions of all atoms with respect to the same interactions with the solvent. ∆G_solvH and ∆G_solvP is the difference in

solvation Solvation (or dissolution) describes the interaction of a solvent with dissolved molecules. Both ionized and uncharged molecules interact strongly with a solvent, and the strength and nature of this interaction influence many properties of the ...

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 In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing ...

compared to inter-molecular

formation (with solvent). ∆G_wb is the extra stabilizing free energy provided by a water molecule making more than one

to the protein (water bridges) that cannot be taken into account with non-explicit solvent approximations. ∆G_el is the electrostatic contribution of charged groups, including the

helix A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is formed as two intertwined helices, ...

dipole. ∆S_mc is the

entropy Entropy is a scientific concept, as well as a measurable physical property, that is most commonly associated with a state of disorder, randomness, or uncertainty. The term and the concept are used in diverse fields, from classical thermodynam ...

cost for fixing the backbone in the folded state. This term is dependent on the intrinsic tendency of a particular

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

to adopt certain dihedral angles. ∆S_sc is the entropic cost of fixing a side chain in a particular conformation. The energy values of ∆G_vdw, ∆G_solvH, ∆G_solvP and ∆G_hbond attributed to each atom type have been derived from a set of experimental data, and ∆S_mc and ∆S_sc 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 : ∆∆G_ab = ∆G_ab- (∆G_a + ∆G_b) + ∆G_kon + ∆S_sc ∆G_kon reflects the effect of electrostatic interactions on the k_on. ∆S_sc is the loss of translational and rotational entropy upon making the complex.

Key features

* ''RepairPDB'':

energy minimization In the field of computational chemistry, energy minimization (also called energy optimization, geometry minimization, or geometry optimization) is the process of finding an arrangement in space of a collection of atoms where, according to some com ...

of a

protein structure Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, the monomers of the polymer. A single amino acid monomer ma ...

* ''BuildModel'': in silico

mutagenesis Mutagenesis () is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using la ...

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 In molecular biology, alanine scanning is a site-directed mutagenesis technique used to determine the contribution of a specific residue to the stability or function of a given protein. Alanine is used because of its non-bulky, chemically inert, ...

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 command-line interpreter or command-line processor uses a command-line interface (CLI) to receive commands from a user in the form of lines of text. This provides a means of setting parameters for the environment, invoking executables and pro ...

. 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

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 pr ...

with FoldX can be directly analyzed on screen.

Molecule Parametrization

In version 5.0, the possibility to parametrize previously not recognized molecules in JSON format was added into the software.

External links