CO bonding in hexa‐ and pentacoordinate carboxy‐neuroglobin: A quantum mechanics/molecular mechanics and local vibrational mode study

Abstract

We present a comprehensive investigation on the different role of CO in carboxyneuroglobin (1) as ligand of the heme group in the active site forming a bond with the heme iron and (2) dissociated from the heme group but still trapped inside the active site, focusing on two specific orientations, one with CO perpendicular to the plane defined by the distal histidine of the enzyme (form A) and one with CO located parallel to that plane (form B). Our study includes wild type carboxy-neuroglobin and nine known protein mutations. Considering that the distal histidine interacting with the heme group can adapt two different tautomeric forms and the two possible orientations of the dissociated CO, a total of 36 protein systems were analyzed in this study. Fully optimized geometries and vibrational frequencies were calculated at the QM/MM level, followed by the local mode analysis, to decode CO bond properties.The intrinsic bond strengths derived from the local mode analysis, complemented with NBO and QTAIM data, reveal that the strength of the CO bond, in the hexacoordinate (where CO is a ligand of the heme group) and pentacoordinate (where CO is dissociated from the heme group) scenarios, is dominated by through bond and through space charge transfer between CO and Fe, fine-tuned by electrostatic and dispersion interactions with the side chain amino acids in the distal heme pocket.Suggestions are made as to advise on how protein modifications can influence the molecular properties of the coordinated or dissociated CO, which could serve the fine-tuning of existing and the design of new neuroglobin models with specific FeC and CO bond strengths.

The Local Vibrational Mode Theory and Its Place in the Vibrational Spectroscopy Arena

“…157 Utilizing the same computational protocol as applied in our MbCO study 137 we investigated CO bonding in hexacoordinate (CO ligated to Fe) and penta-coordinate (CO dissociated from the heme group but trapped in the active site) scenarios for the wild type NgbCO and nine known protein mutations, see Supporting Information for details. 169 In contrast to MbCO we found a less pronounced correlation between the CO and FeC bond strength, see Figure 3a. Further interesting details are revealed by the CNM analysis shown in Figure 3b.…”

“…In three recent studies applying LMA and a hybrid QM/MM methodology, we could for the first time (i) quantify the suggested inverse correlation between the CO and FeC bond strength and the special role of CO···H bonding in Mb and (ii) successfully clarify the binding mode of azanone (HNO) to the heme group of Mb, a long debated question . Utilizing the same computational protocol as applied in our MbCO study we investigated CO bonding in hexacoordinate (CO ligated to Fe) and penta-coordinate (CO dissociated from the heme group but trapped in the active site) scenarios for the wild type NgbCO and nine known protein mutations, see Supporting Information for details . In contrast to MbCO we found a less pronounced correlation between the CO and FeC bond strength, see Figure a.…”

Automatic Generation of Local Vibrational Mode Parameters: From Small to Large Molecules and QM/MM Systems

“…Text examples 9 and 10 were previously reported by our group as qualified vibrational Stark effect probes with highly localized CO NVMs. Whereas the FeC and CO bond strengths in hexacoordinate carboxy-myoglobin and in hexa- and pentacoordinate carboxy-neuroglobin were previously successfully investigated by us, ACS and CNM procedures were not feasible. However, for the first time with LModeAGen, these ACS and CNM procedures for QM/MM systems are now possible.…”

“…35 LModeAGen automatically generated for test example 8, triphenyl phosphate, 12 different groups of quasi-degenerate LVMs adiabatically connected to 108 LVMs, as shown in 35 with highly localized CO NVMs. Whereas the FeC and CO bond strengths in hexacoordinate carboxy-myoglobin 36 and in hexa-and pentacoordinate carboxy-neuroglobin 70 were previously successfully investigated by us, ACS and CNM procedures were not feasible. However, for the first time with LModeAGen, 17), which are quasi-degenerate in test example 10 (Figure 18) and nondegenerate in test example 11 (Figure 19).…”

Quantum Mechanical Assessment of Protein–Ligand Hydrogen Bond Strength Patterns: Insights from Semiempirical Tight-Binding and Local Vibrational Mode Theory

“…[ 133 ], and hydrogen bonds [ 30 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 ]. Recently, the quantitative assessment of bond strength in biological systems applying a QM/MM methodology [ 143 , 144 , 145 ] and the analysis of bonding in actinide and lanthanide compounds have been added to the LMA repertoire [ 146 , 147 , 148 ]. LMA also successfully revised a number of concepts, such as the characterization of metal-ligand interactions, replacing the Tolman electronic parameter (TEP) with the more accurate metal-ligand electronic parameter (MELP), based on local mode force constants [ 149 , 150 , 151 , 152 , 153 ].…”