In silico protein modeling: possibilities and limitations

Rapid advancements in the post-genomic era along with the introduction of novel sequencing technologies provided an even platform for the researchers around the world to sequence new protein and nucleotide sequences in a faster and efficient manner. April 16, 2014 release of UniProtKB database reports about 544996 protein sequence entries for SwissProt unmatched with the way the structures of proteins have been deciphered experimentally during the same tenure. April 16, 2014 data of the Protein data bank reports around 99472 macromolecular structures being determined and submitted in the database with its 92.6 % share of protein structures Of which 88.5 % were deciphered by X-ray crystallography (XRD) followed by 10.4 % using Solution NMR and rest with other techniques like Electron Microscopy, Neutron Diffraction etc. The fundamental biological concept of " Sequence implies the Structure and Structure implies the Function " deciphers that this increase in the amount of sequence knowledge does not reflects any biological significance until the structure of the protein is identified. Criticality the biological function of a protein is totally dependent on its native 3D structure. Frequently applied protein structure determination techniques viz. XRD or NMR are nevertheless quite accurate but highly expensive and overwhelming venture (Schmidt and Lamzin, 2002). Furthermore the technical limitations of proteins resisting the purification process or upholding their native state after crystallization projects towards the pressing need for predicting protein structures computationally (Aloy and Russell, 2006). Different methods have been employed for predicting the 3D structures of protein which can be broadly categorized as a) Homology modeling b) Threading or Fold recognition and c) ab initio methods. Homology modeling also designated as Comparative modeling constructs the unknown structure of the target protein by comparing and utilizing the available information of its ≥ 50 % homologous protein sequence (Sali and Blundell, 1993). The method is highly reliable on the sequence similarity with limited errors in side chains and loop positioning. Homology build structures are analogous to typically resolved structures by NMR. Threading based methods employ the sequence – structure alignment strategy and fold assignments methods when the sequence similarity falls below the desired range of homology modeling technique (Wu and Zhang, 2007). Selected protein 514 structures from databases such as PDB, FSSP, SCOP or CATH after removing proteins with high sequence similarity act as structural templates for the alignment. The unavailability of suitable template for modeling dictates towards the use of ab …