Loop modeling is a problem in protein structure prediction

Protein structure prediction

Protein structure prediction is the prediction of the three-dimensional structure of a protein from its amino acid sequence — that is, the prediction of its secondary, tertiary, and quaternary structure from its primary structure. Structure prediction is fundamentally different from the inverse...

 requiring the prediction of the conformations of loop regions in 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...

s without the use of a structural template. The problem arises often in 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...

, where the tertiary structure

Tertiary structure

In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...

 of an amino acid sequence is predicted based on a sequence alignment

Sequence alignment

In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Aligned sequences of nucleotide or amino acid residues are...

 to a template, or a second sequence whose structure is known. Because loops have highly variable sequences even within a given structural motif

Structural motif

In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...

 or protein fold

Protein 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....

, they often correspond to unaligned regions in sequence alignments; they also tend to be located at the solvent

Solvent

A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...

-exposed surface of globular protein

Globular protein

Globular proteins, or spheroproteins are one of the two main protein classes, comprising "globe"-like proteins that are more or less soluble in aqueous solutions...

s and thus are more conformationally flexible. Consequently, they often cannot be modeled using standard homology modeling techniques. More constrained versions of loop modeling are also used in the data fitting stages of solving a protein structure by X-ray crystallography

X-ray crystallography

X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...

, because loops can correspond to regions of low electron density

Electron density

Electron density is the measure of the probability of an electron being present at a specific location.In molecules, regions of electron density are usually found around the atom, and its bonds...

 and are therefore difficult to resolve.

Regions of a structural model that were predicted by loop modeling tend to be much less accurate than regions that were predicted using template-based techniques. The extent of the inaccuracy increases with the number of 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...

s in the loop. The loop amino acids' side chain

Side chain

In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...

s dihedral angle

Dihedral angle

In geometry, a dihedral or torsion angle is the angle between two planes.The dihedral angle of two planes can be seen by looking at the planes "edge on", i.e., along their line of intersection...

s are often approximated from a rotamer library, but can worsen the inaccuracy of side chain packing in the overall model. Andrej Sali

Andrej Šali

Andrej Šali is a computational structural biologist. He joined the faculty of the Rockefeller University in 1995, following his postdoctoral research at Harvard University...

's homology modeling suite MODELLER

MODELLER

MODELLER is a computer program used in producing homology models of protein tertiary structures as well as quaternary structures . It implements a technique inspired by nuclear magnetic resonance known as satisfaction of spatial restraints, by which a set of geometrical criteria are used to create...

 includes a facility explicitly designed for loop modeling by a satisfaction of spatial restraints method.

Short loops

In general, the most accurate predictions are for loops of fewer than 8 amino acids. Extremely short loops of three residues can be determined from geometry alone, provided that the bond lengths and bond angles are specified. Slightly longer loops are often determined from a "spare parts" approach, in which loops of similar length are taken from known crystal structures and adapted to the geometry of the flanking segments. In some methods, the bond lengths and angles of the loop region are allowed to vary, in order to obtain a better fit; in other cases, the constraints of the flanking segments may be varied to find more "protein-like" loop conformations. The accuracy of such short loops may be almost as accurate as that of the homology model upon which it is based. It should also be considered that the loops in proteins may not be well-structured and therefore have no one conformation that could be predicted; NMR experiments indicate that solvent-exposed loops are "floppy" and adopt many conformations, while the loop conformations seen by X-ray crystallography

X-ray crystallography

X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...

may merely reflect crystal packing interactions, or the stabilizing influence of crystallization co-solvents.

External links

• MODLOOP, public server for access to MODELLER's loop modeling facility