Computer simulation of collision induced dissociation and isolobal analogy: The case of biotin and its analogs

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Highlights

  • Chemical dynamics simulations show that isolobal analogs have similar fragmentation patterns.

  • Simulations reproduce fragmentation pattern available for biotin in database.

  • Simulations identify the fragmentation mechanisms and determine how the modified compounds behave differently.

  • Results show that it would be possible to predict MS/MS spectra of isolobal analog species if one is known.

Abstract

We have studied how collision induced dissociation (CID) products and associated mechanisms change when a chemical group is modified by isolobal substitution, and in particular the sequence S, O, NH and CH2. At this end, we have considered protonated biotin (vitamin B7) and corresponding oxybiotin, N-biotin and C-biotin, which have the same structures except for one chemical group (the S in biotin which is substituted with the aforementioned isolobal ones). Collisional simulations with Ar were performed to model CID fragmentations and to have direct access to related mechanisms. Simulations show that the CID fragmentation of the four compounds are similar and the resulting fragments involve in a similar way the isolobal groups. Details on the mechanisms obtained from simulations are reported and discussed. This result shows that it is possible to predict, in principle and with a reasonable confidence, mass spectra of unknown molecules based on mass spectrum of a known one when isolobal modifications are done.

Introduction

The concept of isolobal analogy was introduced years ago by Hoffmann as a practical tool to understand and easily predict organic and organometallic reactions [1]. In the original publication, discussing the properties of M(CO)3 and M(C6H6) (where M is a metal) they “mean to imply that the number, symmetry properties, extent in space and energy of the frontier orbitals of the fragments are similar – not identical, but similar” [2]. Thus, two compounds, where one chemical group is replaced by another with similar properties in the frontier orbitals, are expected to behave similarly. In mass spectrometry, this concept could be used to predict fragmentation patterns of molecules which are derived from a known one where a group is replaced by an isolobal one.

Understanding and even better predicting fragmentation patterns in collision induced dissociation (CID) is crucial in both fundamental and practical applications of mass spectrometry. One approach consists in library searching, for example using the extended NIST library [3]. Of course, libraries need experiments on all the species of interest and mechanisms can be proposed only for data for which experiments are available. Another approach uses machine learning algorithms to guess fragmentation patterns, like in the competitive fragmentation model (CFM) by Allen et al. which uses a probabilistic generative model [4].

Another possibility to predict CID spectra independently from simulation is to use molecular simulations [5]. This approach, pioneered by Hase and co-workers [6,7], was then extended in last 10 years to a variety of biological and organic molecules [8]. The same approach can be successfully used to model and predict surface induced dissociation and soft landing [9,10]. It is based on two alternative physical representations of the collisional activation: (1) by providing an excess energy equally distributed through the vibrational modes of the fragmenting molecule, (2) by direct simulating the collision with the inert gas [11,12]. Since it is based on the generation of an ensemble of reactive trajectories, the chemical dynamics approach provides at the same time the fragmentation products and the related mechanisms. The most relevant drawback is that it requires significant computational effort, and thus for relatively large systems highly accurate quantum chemistry methods cannot be used. However, semi-empirical Hamiltonians have shown to be able to provide relatively good fragmentation patterns and mechanisms [[13], [14], [15], [16]], in particular for organic and rigid molecules, like testosterone [17] or methyl-guanine [18]. In this last study, a comparison with CFM machine learning prediction was done, showing that the chemical trajectory approach is comparable with it, providing at the same time more information on reaction mechanisms and physically ground results.

Here, we have investigated the CID fragmentation in relation with the isolobal analogy. In particular we have considered protonated biotin (also called vitamin B7 or H) and then substituted the S atom with O (oxybiotin), NH (N-biotin) and CH2 (C-biotin), forming a set of compounds shown in Fig. 1. These atoms and fragments fulfill the “isolobal analogy” prescription since their frontier orbitals have similar energy, shape and number of electrons [1].

Other than a chemical rationale in modifying the S atom of biotin, there is also a biological interest on it. In fact, biotin acts as a coenzyme for carboxylase enzymes, involved in the synthesis of fatty acids, isoleucine, and valine, and in gluconeogenesis [19,20]. If there is insufficient biotin in a higher organism, oxybiotin is the only analog capable of replacing it [21]. In general, single site substitution is common in biology and it can be useful to predict mass spectra of possible analogs independently from experiments. We have thus considered these four molecules, activated by modeling explicit collision with Ar atom and analyzed product ions and mechanisms. In particular, we focused on how the fragmentation spectra is (eventually) modified in the isolobal analogs and which are the related mechanisms. This will provide a guide to possibly predict the CID of different isolobal species from the spectrum of a known one.

Section snippets

Reactant structures

Biotin has an imidazolidinone structure and thiolane ring (Fig. 1a). The isolobal analogs considered here are: oxybiotin, N-biotin and C-biotin. They have the same structure as biotin but S is substituted by O, NH, CH2 (also shown in Fig. 1). Although N-biotin and C-biotin are hypothetical molecules, these two compounds provide optimal examples to study isolobal analogy on CID products and mechanisms.

Protonation can occur on different basic sites: six for biotin, oxybiotin and N-biotin and five

Ar-S interaction potential parameters

The interaction potential between Ar and S bound to two carbon atoms (C-S-C) in thiolane was obtained by performing QCISD(T)/6–31++G(d,p) calculations along the Ar…S C2v axis of thiolane. The resulting ab initio energy curve is plotted in Fig. 3 together with the result of fitted Equation (2). Corresponding parameters for Ar-S interaction are reported in Table 1.

Proton affinities

Proton affinities are calculated for each stable tautomer of biotin and isolobal analogs. In this way, it is possible to determine the

Conclusions

In this work, we have studied how protonated biotin and isolobal analogs oxybiotin, C-biotin and N-biotin fragment in CID simulations. Experiments are available only for biotin and simulations have shown a good agreement, being able to elucidate the different fragmentation mechanisms. The isolobal analogs seem to react in a similar way, in particular for the characteristic peaks. Even when the mechanisms involve the isolobal analog part, the final fragmentation products are often the same,

CRediT authorship contribution statement

Yanghune Ha: Investigation, Data curation, Visualization, Writing - original draft. Riccardo Spezia: Data curation, Visualization, Writing - review & editing. Kihyung Song: Conceptualization, Resources, Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Acknowledgments

The authors dedicate this article to the memory of Prof. William (Bill) L. Hase. He inspired us for many years, and we had many fruitful collaborations and scientific discussions. He was a reference and a friend.

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