Serine Protease inhibitors (serpins) are a super-family of proteins that controls the proteinases involved in the
inflammation, complementation, coagulation and fibrinolytic pathways. Serpins are prone to conformational diseases due
to a complex inhibition mechanism that involves large scale conformational change, and their susceptibility to undergo
point mutations might lead to functional defects. Serpins are associated with diseases like emphysema/cirrhosis, angioedema,
familial dementia, chronic obstructive bronchitis and thrombosis. Serpin polymerization based pathologies are
fairly widespread and devising a cure has been difficult due to lack of clarity regarding its mechanism. Serpin can exist in
various conformational states and has a variable cofactor binding ability. It has a large genome and proteome database
which can be utilized to gain critical insight into their structure, mechanism and defects. Comprehensive computational
studies on the serpin family is lacking, most of the work done till date is limited and deals mostly with few individual serpins.
We have tried to analyze few aspect of this family using diverse computational biology tools and have shown the
following: a) the importance of residue burial linked shift in the conformational stability as a major factor in increasing
the polymer propensity in serpins. b) Amino acids involved in the polymerization are in general completely buried in the
native conformation. c) An isozyme specific antithrombin study showed the structural basis of improved heparin binding
to beta antithrombin as compared to alpha-antithrombin. d) A comprehensive cavity analysis showed its importance in inhibition
and polymerizaiton and finally e) an interface analysis of various serpin protease complexes identified critical
evolutionary conserved residues in exosite that determines its protease specificity. This work introduces the problem and
emphasizes on the need for in-depth computational studies of serpin superfamily.
Keywords: Antithrombin, molecular docking, protein cavities, protein polymerization, residue burial, serine protease inhibitors.
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