title: Heterogeneous behavior of metalloproteins toward metal ion binding and selectivity: insights from molecular dynamics studies.
abstract: About one-third of the existing proteins require metal ions as cofactors for their catalytic activities and structural complexities. While many of them bind only to a specific metal, others bind to multiple (different) metal ions. However, the exact mechanism of their metal preference has not been deduced to clarity. In this study, we used molecular dynamics (MD) simulations to investigate whether a cognate metal (bound to the structure) can be replaced with other similar metal ions. We have chosen seven different proteins (phospholipase A2, sucrose phosphatase, pyrazinamidase, cysteine dioxygenase (CDO), plastocyanin, monoclonal anti-CD4 antibody Q425, and synaptotagmin 1 C2B domain) bound to seven different divalent metal ions (Ca(2+), Mg(2+), Zn(2+), Fe(2+), Cu(2+), Ba(2+), and Sr(2+), respectively). In total, 49 MD simulations each of 50 ns were performed and each trajectory was analyzed independently. Results demonstrate that in some cases, cognate metal ions can be exchanged with similar metal ions. On the contrary, some proteins show binding affinity specifically to their cognate metal ions. Surprisingly, two proteins CDO and plastocyanin which are known to bind Fe(2+) and Cu(2+), respectively, do not exhibit binding affinity to any metal ion. Furthermore, the study reveals that in some cases, the active site topology remains rigid even without cognate metals, whereas, some require them for their active site stability. Thus, it will be interesting to experimentally verify the accuracy of these observations obtained computationally. Moreover, the study can help in designing novel active sites for proteins to sequester metal ions particularly of toxic nature.
authors.affiliation: a Department of Biosciences and Bioengineering , Indian Institute of Technology Guwahati , Guwahati , Assam 781039 , India.
authors.forename: Prerana
authors.initials: P
authors.lastname: Gogoi
authors.affiliation: a Department of Biosciences and Bioengineering , Indian Institute of Technology Guwahati , Guwahati , Assam 781039 , India.
authors.forename: Monika
authors.initials: M
authors.lastname: Chandravanshi
authors.affiliation: a Department of Biosciences and Bioengineering , Indian Institute of Technology Guwahati , Guwahati , Assam 781039 , India.
authors.forename: Suraj Kumar
authors.initials: SK
authors.lastname: Mandal
authors.affiliation: a Department of Biosciences and Bioengineering , Indian Institute of Technology Guwahati , Guwahati , Assam 781039 , India.
authors.forename: Ambuj
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: a Department of Biosciences and Bioengineering , Indian Institute of Technology Guwahati , Guwahati , Assam 781039 , India.
authors.forename: Shankar Prasad
authors.initials: SP
authors.lastname: Kanaujia
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D007477:Ions / Q000737:chemistry*; D008667:Metalloproteins / Q000737:chemistry*; D008670:Metals / Q000737:chemistry*; D019216:Metals, Heavy / Q000737:chemistry; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding
chemical_list: D007477:Ions; D008667:Metalloproteins; D008670:Metals; D019216:Metals, Heavy
keywords: active site design; heavy metal ions; molecular dynamics simulation; protein engineering; sequestering toxic metals