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1. Metal–ligand and hydrogen bonding in the active site of Fe( iii )-, Mn( iii )- and Co( iii )-myoglobins

   https://doi.org/10.1039/D4DT03246B  

   Freindorf, Marek; Kraka, Elfi (March 2025, Dalton Transactions)

   We investigated in this work strength of metal–ligand and hydrogen bonding in complexes formed between Fe, Mn, and Co myoglobin and molecular ligands such as methanol, water, nitrite, and azide involving ε and δ protonation forms of distal histidine. 

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2. CO Bonding in Hexa- and Pentacoordinate Carboxy-Neuroglobin - A QM/MM and Local Vibrational Mode Study

   https://doi.org/10.1002/jcc.26973  

   Marek Freindorf, Alexis Antoinette (July 2022, Journal of computational chemistry)

   We present a comprehensive investigation on the different role of CO in carboxy- neuroglobin i) as ligand of the heme group in the active site forming a bond with the heme iron and ii) 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. 

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3. Halogen Bonding Involving I2 and d8 Transition-Metal Pincer Complexes

   https://doi.org/10.3390/cryst11040373  

   Freindorf, Marek; Yannacone, Seth; Oliveira, Vytor; Verma, Niraj; Kraka, Elfi (April 2021, Crystals)

   We systematically investigated iodine–metal and iodine–iodine bonding in van Koten’s pincer complex and 19 modifications changing substituents and/or the transition metal with a PBE0–D3(BJ)/aug–cc–pVTZ/PP(M,I) model chemistry. As a novel tool for the quantitative assessment of the iodine–metal and iodine–iodine bond strength in these complexes we used the local mode analysis, originally introduced by Konkoli and Cremer, complemented with NBO and Bader’s QTAIM analyses. Our study reveals the major electronic effects in the catalytic activity of the M–I–I non-classical three-center bond of the pincer complex, which is involved in the oxidative addition of molecular iodine I2 to the metal center. According to our investigations the charge transfer from the metal to the σ* antibonding orbital of the I–I bond changes the 3c–4e character of the M–I–I three-center bond, which leads to weakening of the iodine I–I bond and strengthening of the metal–iodine M–I bond, facilitating in this way the oxidative addition of I2 to the metal. The charge transfer can be systematically modified by substitution at different places of the pincer complex and by different transition metals, changing the strength of both the M–I and the I2 bonds. We also modeled for the original pincer complex how solvents with different polarity influence the 3c–4e character of the M–I–I bond. Our results provide new guidelines for the design of pincer complexes with specific iodine–metal bond strengths and introduce the local vibrational mode analysis as an efficient tool to assess the bond strength in complexes. 

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4. Hydrogen Bonding in Natural and Unnatural Base Pairs—A Local Vibrational Mode Study

   https://doi.org/10.3390/molecules26082268  

   Beiranvand, Nassim; Freindorf, Marek; Kraka, Elfi (April 2021, Molecules)

   In this work hydrogen bonding in a diverse set of 36 unnatural and the three natural Watson Crick base pairs adenine (A)–thymine (T), adenine (A)–uracil (U) and guanine (G)–cytosine (C) was assessed utilizing local vibrational force constants derived from the local mode analysis, originally introduced by Konkoli and Cremer as a unique bond strength measure based on vibrational spectroscopy. The local mode analysis was complemented by the topological analysis of the electronic density and the natural bond orbital analysis. The most interesting findings of our study are that (i) hydrogen bonding in Watson Crick base pairs is not exceptionally strong and (ii) the N–H⋯N is the most favorable hydrogen bond in both unnatural and natural base pairs while O–H⋯N/O bonds are the less favorable in unnatural base pairs and not found at all in natural base pairs. In addition, the important role of non-classical C–H⋯N/O bonds for the stabilization of base pairs was revealed, especially the role of C–H⋯O bonds in Watson Crick base pairs. Hydrogen bonding in Watson Crick base pairs modeled in the DNA via a QM/MM approach showed that the DNA environment increases the strength of the central N–H⋯N bond and the C–H⋯O bonds, and at the same time decreases the strength of the N–H⋯O bond. However, the general trends observed in the gas phase calculations remain unchanged. The new methodology presented and tested in this work provides the bioengineering community with an efficient design tool to assess and predict the type and strength of hydrogen bonding in artificial base pairs. 

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5. Iron‐Histidine Coordination in Cytochrome b5: A Local Vibrational Mode Study

   https://doi.org/10.1002/cphc.202401098  

   Freindorf, Marek; Fleming, Kevin; Kraka, Elfi (February 2025, ChemPhysChem)

   Abstract For a series of cytochrome b5 proteins isolated from various species, including bacteria, animals, and humans, we analyzed the intrinsic strength of their distal/proximal FeN bonds and the intrinsic stiffness of their axial NFeN bond angles. To assess intrinsic bond strength and bond angle stiffness, we employed local vibrational stretching force constants k^a(FeN) and bending force constants k^a(NFeN) derived from the local mode theory developed by our group; the ferric and ferrous oxidation states of the heme Fe were considered. All calculations were conducted with the QM/MM methodology. We found that the reduction of the heme Fe from the ferric to the ferrous state makes the FeN axial bonds weaker, longer, less covalent, and less polar. Additionally, the axial NFeN bond angle becomes stiffer and less flexible. Local mode force constants turned out to be far more sensitive to the protein environment than geometries; evaluating force constant trends across diverse protein groups and monitoring changes in the axial heme‐framework revealed redox‐induced changes to the primary coordination sphere of the protein. These results indicate that local mode force constants can serve as useful feature data for training machine learning models that predict cytochrome b5 redox potentials, which currently rely more on geometric data and qualitative descriptors of the protein environment. The insights gained through our investigation also offer valuable guidance for strategically fine‐tuning artificial cytochrome b5 proteins and designing new, versatile variants. 

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