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.

Computational insights into pH‐dependence of structure and dynamics of pyrazinamidase: A comparison of wild type and mutants

“…The mechanism of PZA catalysis by Mycobacterium tuberculosis PZase is centered on deprotonation of the C138 thiol group, which is stabilized and activated by K96 and D8, respectively . Both experimental and theoretical studies have indicated that altering Fe 2+ /Zn 2+ with other divalent metal ions, such as Mn 2+ , Co 2+ , Sr 2+ , Ba 2+ , Fe 3+ , Mg 2+ , and Ca 2+ , cannot strongly change the activity and stability of PZase, that is, the enzyme shows stability coordinating each of the ions at the MCS. A rare cis‐peptide bond exists in PZase between I133 and A134, making possible the formation of an oxyanion hole between the amine group of A134 and C138, which is also observable in pyrazinamidase from P. horikoshii and Acinetobacter baumanii .…”

Better force fields start with better data: A data set of cation dipeptide interactions

“…Gogoi et al . investigated protein-metal ion binding affinities by analysing MD simulations of 49 different cation-protein complexes 6 . Metal cations can alter peptide structure by interacting with backbones and thereby enforcing non-Ramachandran geometries 7 .…”

Computational analysis of the metal selectivity of matrix metalloproteinase 8

“…Metal coordination chemistry requires the use of quantum mechanics (QM) simulations, for the traditional force fields have not been able to completely address the chemistry around these metal co-factors [29]. Previous study has identified the presence/absence of metal binding selectivity in various type of divalent metal metalloproteins using molecular dynamics simulations, this approach, however, does not provide enough accuracy in comparisons of structural differences induced by different divalent metal cofactors [30]. Density functional theory (DFT) has been applied to the studies of protein, which provides sufficient computational efficiency as well as accuracy.…”