Protein Structure Prediction
From DrugPedia: A Wikipedia for Drug discovery
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[edit] Ab initio Method
Ab-initio or de novo is used when no sequence or structural similarity is detected.This is a method of predicting the protein structure only from sequence.There are many possible procedures that either attempt to mimic protein folding or apply some stochastic method to search possible solutions (i.e., global optimization of a suitable energy function).These ab initio or energy minimization methods are based on the hypothesis that native structure of protein has minimum free energy. Energy-based methods don’t make a priori assumptions about the coding properties of amino acids, but attempt to locate the global minima in free energy surface of the protein molecule. The conformation having minimum free energy is considered as the native conformation of the protein.
These methods can be classified broadly in two categories
- Static minimization methods
- Dynamic minimization methods
Energy calculations offer the advantage of being based on physicochemical principles but are hampered by the large number of degrees of freedom to be considered and the limited performance of energy functions.
There are three major drawbacks of methods based on energy calculations.
- The computation power required for energy minimization is beyond the reach of presently available computers.
- The interaction potentials used for such calculations are not good enough to model the native structure of a protein at atomic detail.
- The knowledge about the interactions that contribute to protein stability is still very limited.
To predict protein structure de novo for larger proteins will require better algorithms and larger computational resources like those afforded by either powerful supercomputers (such as Blue Gene or MDGRAPE-3) or distributed computing (such as Folding@home, the Human Proteome Folding Project and Rosetta@Home). Although these computational barriers are vast, the potential benefits of structural genomics (by predicted or experimental methods) make ab initio structure prediction an active research field.
As an intermediate step towards predicted protein structures, contact map predictions have been proposed.
[edit] Comparative Modeling
This is a method of protein structrue prediction that is based on previously solved protein structure used as a templete for building model.his is effective because it appears that although the number of actual proteins is vast, there is a limited set of tertiary structural motifs to which most proteins belong. It has been suggested that there are only around 2000 distinct protein folds in nature, though there are many millions of different proteins.
These methods may also be split into two groups:
Threading scans the amino acid sequence of an unknown structure against a database of solved structures. In each case, a scoring function is used to assess the compatibility of the sequence to the structure, thus yielding possible three-dimensional models. This type of method is also known as 3D-1D fold recognition due to its compatibility analysis between three-dimensional structures and linear protein sequences.
Homology Modeling is based on the principle that if two sequence have similarity more than 30% they must share structure similarity.
