An integrated platform for automatic design and screening of virtual mutants based on 3D-QSAR analysis

• Published in: Journal of Molecular Catalysis B: Enzymatic
• Main Authors: FERRARIO, VALERIO, EBERT, CYNTHIA, GARDOSSI, Lucia, Svendsen A., Besenmatter W.
• Other Authors: Ferrario, Valerio, Ebert, Cynthia, Svendsen, A., Besenmatter, W., Gardossi, Lucia
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2014
• Subjects: computational chemistry; enzyme engineering; 3DQSAR; biocatalysi; lipase; amidases; Antarc*; Antarctica
• Online Access: http://hdl.handle.net/11368/2744899; https://doi.org/10.1016/j.molcatb.2013.12.004

tAn innovative application of 3D-QSAR methodology to the rational design of enzymes is here reported.The introduction of amidase activity inside the scaffold of lipase B from Candida antarctica (CaLB) wasstudied and 3D-QSAR models were constructed to correlate the structures of a set of CaLB mutants withtheir experimentally measured activities. Properties, like hydrophilicity, hydrophobicity and hydrogenbonding capability of the enzyme active site were computed by means of the GRID method and theoutput was used as molecular descriptors. Correlations with experimental behavior of the catalysts werecalculated by means of partial least square regression (PLS). The analysis of the QSAR model fully exploitsfundamental knowledge while avoiding conceptual biases. Rationales for driving enzyme engineeringare disclosed and a priori evaluation of new virtual candidate mutants becomes feasible. On that respect,the whole procedure for production of virtual mutants and scoring of their activity was automated withina workflow constructed by means of the modeFRONTIER package. The method allows for the automatedconstruction and scoring of each mutant in 2 h on a normal workstation.