Phospholipase A2-IIA catalyzes the hydrolysis of the sn-2 ester of glycerophospholipids. A rare c.428G > A (p.Arg143His) variant in PLA2G2A gene was found in two infants affected by acute respiratory distress syndrome (ARDS) by whole coding region and exon/intron boundaries sequencing. To obtain insights into the possible molecular effects of the rare R123H mutation in secretory PLA2-IIA (sPLA2-IIA), molecular modelling, molecular dynamics (MD) using principal component analysis (PCA) and continuum electrostatic calculations were conducted on the crystal structure of the wild type protein and on a generated model structure of the R123H mutant. Analysis of MD trajectories indicate that the overall stability of the protein is not affected by this mutation but nevertheless the catalytically crucial H -bond between Tyr51 and Asp91 as well as main electrostatic interactions in the region close to the mutation site are altered. PCA results indicate that the R123H replacement alter the internal molecular motions of the enzyme and that collective motions are increased. Electrostatic surface potential studies suggest that after mutation the interfacial binding to anionic phospholipid membranes and anionic proteins may be changed. The strengthening of electrostatic interactions may be propagated into the active site region thus potentially affecting the substrate recognition and enzymatic activity. Our findings provide the basis for further investigation and advances our understanding of the effects of mutations on sPLA2 structure and function.

Righino, B., Minucci, A., Pirolli, D., Capoluongo, E., Conti, G., De Luca, D., De Rosa, M., In silico investigation of the molecular effects caused by R123H variantin secretory phospholipase A2-IIA associated with ARDS, <<JOURNAL OF MOLECULAR GRAPHICS & MODELLING>>, 2018; 81 (81): 68-76. [doi:10.1016/j.jmgm.2018.02.014] [http://hdl.handle.net/10807/121529]

In silico investigation of the molecular effects caused by R123H variant in secretory phospholipase A2-IIA associated with ARDS

Righino, B;Minucci, A;Pirolli, D;Capoluongo, E;Conti, G;De Luca, D;De Rosa, Mc
2018

Abstract

Phospholipase A2-IIA catalyzes the hydrolysis of the sn-2 ester of glycerophospholipids. A rare c.428G > A (p.Arg143His) variant in PLA2G2A gene was found in two infants affected by acute respiratory distress syndrome (ARDS) by whole coding region and exon/intron boundaries sequencing. To obtain insights into the possible molecular effects of the rare R123H mutation in secretory PLA2-IIA (sPLA2-IIA), molecular modelling, molecular dynamics (MD) using principal component analysis (PCA) and continuum electrostatic calculations were conducted on the crystal structure of the wild type protein and on a generated model structure of the R123H mutant. Analysis of MD trajectories indicate that the overall stability of the protein is not affected by this mutation but nevertheless the catalytically crucial H -bond between Tyr51 and Asp91 as well as main electrostatic interactions in the region close to the mutation site are altered. PCA results indicate that the R123H replacement alter the internal molecular motions of the enzyme and that collective motions are increased. Electrostatic surface potential studies suggest that after mutation the interfacial binding to anionic phospholipid membranes and anionic proteins may be changed. The strengthening of electrostatic interactions may be propagated into the active site region thus potentially affecting the substrate recognition and enzymatic activity. Our findings provide the basis for further investigation and advances our understanding of the effects of mutations on sPLA2 structure and function.
Inglese
Righino, B., Minucci, A., Pirolli, D., Capoluongo, E., Conti, G., De Luca, D., De Rosa, M., In silico investigation of the molecular effects caused by R123H variantin secretory phospholipase A2-IIA associated with ARDS, <<JOURNAL OF MOLECULAR GRAPHICS & MODELLING>>, 2018; 81 (81): 68-76. [doi:10.1016/j.jmgm.2018.02.014] [http://hdl.handle.net/10807/121529]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/121529
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