ABIO

Introduction

Although there are drawbacks to invoking silicon as the basis for life, some silicon-based chemicals have been found to be more stable than the equivalent hydrocarbons in sulfuric acid-rich and sulfur-rich environments [1-11]. The idea that life could be based on silicon rather than carbon was first proposed in 1891 by the German astrophysicist Julius Scheiner [12]. There are diatoms which exist in nature and contain silicon for structural integrity [10]. Of the molecules identified in interstellar space, 84 are carbon-based and 8 are silicon-based [5]. In addition, the ratio of abundance of silicon to carbon in the earth’s crust is 925 to one, whereas the cosmic ratio of carbon to silicon is 10 to one [5]. Silicon has a larger atomic radius and larger mass than carbon. Currently, silicon lacks the chemical versatility in forming stable bonds required for known biochemical metabolism on earth. Long chain silanes spontaneously decompose and are often highly reactive with water. Silicones (containing Si-O-Si) however, are very stable. No one has yet isolated a stable silicon analogue of a pure protein amide bond, although attempts to isolate a silicon-based polypeptide are in progress [6,7]. The unusual structure of disilyne (Si₂H₂) predicted theoretically, showed the ability of silicon-hydrides to adopt unique structures [1,2,13]. We examined a series of silicon analogues of carbon-based molecules of biochemical interest and compared the relative minimized energies and structures of our selected molecules with their carbon counterparts. Our results present some silicon structures that although may offer alternatives to carbon-based life (extremophiles) in extreme environments, non-aqueous solvents, and interstellar space, these computergenerated structures demonstrate the innate difficulty of silicon in forming strong pπ-pπ bonds required for many required functional biomolecules on Earth.

Background-A Comparison of Carbon and Silicon Properties

An excellent and comprehensive 2020 paper on the topic of silicon by Petkowski, Bains, and Seager [11] concluded that purely silicon-based life is highly unlikely in most planetary environments, particularly those with water, suggesting silicon may serve as a minor structural component in extreme conditions. The study systematically explored the possibility of silicon serving as a building block of life and evaluated the potential of silicon as a biological scaffold in various solvents using a combinatorial approach [14]. Our studies herein are based upon the theoretical study of silicon-substituted biomolecules with respect to steric, geometric, and energetic considerations. Silicon is the closest analogue of carbon. Silicon and carbon are tetravalent atoms that form primarily covalent compounds. However, from a chemical and biochemical perspective, there is little similarity between Si and C that goes beyond the statement learned in organic chemistry that both elements “can form four covalent bonds” [11]. The covalent radius of a silicon atom is larger than that of carbon which results in generally longer bond lengths and different bond angles (Table 1).

Table 1: Comparative Physical and Chemical Properties of Carbon and Silicon.

Different bond lengths and angles have especially large effects in ring structures containing silicon atoms, resulting in distinct ring conformation as compared to their carbon-containing analogues. In our computational research, these large effects in ring structures and distinct ring conformations containing silicon atoms were seen in the comparison of the energy-minimized structures of Fe⁺²protoporphyrin IX containing carbon versus silicon atoms in the molecule See (Figures 1 and 2).

Figure 1: Lowest energy geometry for Fe⁺²-protophoryin IX with carbon atoms in light blue. Note the planar porphyrin ligand with four planar pyrrole rings. E_min=5726.124 kJ/mol.

Figure 2: Lowest energy geometry for Fe⁺²-protophoryin IX with silicon atoms (grey) substituted for carbon atoms. Note the non-planar porphyrin ligand with four twisted pyrrole rings. E_min=11209.94 kJ/mol.

From a bonding perspective, silicon has the availability of lowlying 3d orbitals that allow silicon to form compounds with five- or six-coordinated silicon atoms that carbon is unable to achieve [15-17]. Silicon is more electropositive (and less electronegative) as compared to C, N, O, and H. The higher electropositivity (and lower electronegativity) of Si creates an electron-deficient center in silicon and results in a stronger bond polarization as compared to analogous carbon bonds, or in a reversed bond polarization of the C-H and Si-H bonds (Table 1). As a result of those differences, most bonds that silicon forms with non-metals are more strongly polarized than their carbon counterparts and thus more susceptible to electrophilic and nucleophilic attack. For example, silicon tetrachloride (SiCl₄) is hydrolyzed almost instantly in water, whereas carbon tetrachloride (CCl₄), is stable for years in the presence of water. Silanes (SiH₄, Si₂H₆, etc.) are stable as pure chemicals for years but are very sensitive to water in the presence of trace alkali. Reactions of disilane (Si₂H₆) and ethane (C₂H₆) with oxygen are exothermic, but ethane (C₂H₆) can mix with oxygen at 200 °C without reacting, whereas disilane (Si₂H₆) spontaneously combusts in air at 0 °C [17]. An extensive overview of the physical and chemical properties of carbon and silicon, including their respective bond and common functional group reactivity can be found at: Petkowski, JJ, Bains, W, and Seager, S. (2020) On the Potential of Silicon as a Building Block for Life, Life (Basel)2020 Jun 10;10(6):84.

Experimental Methods

The method of investigation used HyperChem 8.0.10 and Spartan ’06 molecular mechanics software to build carbon-based biomolecules commonly found in nature, and then calculate minimized energies, necessary bond lengths, dipole moments, and bond angles. Each molecule being investigated was built from scratch, replacing the carbon atoms with silicon atoms. The same calculations were carried out, and the results compared. Additionally, a comparison of methane and silane was carried out to assess our methods. Geometric optimization, minimized energies, bond angles and vibrational analysis were performed on each molecule.

Selection of Molecules for Study

(Figure 3) lists and depicts the fifteen (15) carbon molecules selected for our study. These molecules were selected based upon their representation in chemistry and biochemistry and pharmacology as important biomolecules. Fifteen (15) additional molecules were studied, each of which was the silicon analogue of the corresponding carbon molecule. Molecules 1-6 are classical organic molecules, which also have accessible silicon analogues, either experimentally and/or theoretically for comparison. Molecules 7-15 were selected for the following reasons:

Molecule 7-Adenosine triphosphate is a molecule that carries energy for cellular processes and is often called the “energy currency” of the cell. It is generated through cellular respiration and provides energy for essential functions like muscle contraction, nerve impulses, and chemical synthesis.

Molecules 8 and 9-Caffeine and glucose are chemicals that play important roles in the human body. Glucose is a simple sugar and a primary source of energy for the body’s cells, produced from the carbohydrates in food. It is transported to cells via the bloodstream, and its levels are regulated by hormones like insulin. Caffeine is a central nervous stimulant and acts by blocking the binding of adenosine at a number of adenosine receptor types, inhibiting the centrally depressant effects of adenosine and enhancing the release of acetylcholine. Caffeine has a three-dimensional structure similar to that of adenosine, which allows it to bind and block its receptors.

Molecules 10-12: Fe⁺²-protoporphyrin IX serves as an active site for many heme proteins. Oxytocin is a natural hormone and polypeptide composed of nine amino acids connected by peptide bonds. It stimulates uterine contractions in childbirth and lactation after infant birth. It also affects aspects of human behavior and the male and female reproductive systems. Fe⁺²-tetraphenylporphyrin serves as a model compound for hemeproteins and is used widely in porphyrin chemistry.

Molecules 13-15: These molecules (acetaminophen, propofol, and cocaine) were selected as representatives of drugs used by humans. Acetaminophen is a popular pain killer. Propofol is a short-acting intravenous anesthetic used for general anesthesia and sedation in medical procedures and intensive care. It works by enhancing the inhibitory effects of the neurotransmitter GABA in the central nervous system, leading to a rapid onset and recovery from its effects. Cocaine is a central nervous system stimulant and tropane alkaloid derived primarily from the leaves of two coca species native to South America.

 Figure 3: Carbon Molecules Selected for Study.

Results and Discussion

Our computational study of fifteen silicon analogues of selected carbon molecules resulted in comparative minimized energies and global minima geometries of thirty different molecules. Out of the 30 molecules studied, seven of the fifteen silicon analogues exhibited higher minimized energies than the parent carbon molecules. These molecules are highlighted in yellow on  (Table 2).

Table 2: Minimized energies of carbon and silicon molecules studied and energy differences calculated using HyperChem 8.0.10 and Spartan ’06.

These seven molecules include Si₂H₂ (disilyne), Si₆H_12, Si₁₀H₁₆N₅O₁₃P₁₃ (Si-ATP), Si₃₄H₃₄FeN₄O₄ (Fe-SiPPIX), Si₄₄H₂₈FeN₄ (FeSiTPP), Si₁₂H₁₈O (Si-propofol), and Si₁₇H₂₁NO (Si-cocaine). These all had nonplanar and sometimes twisted geometries See (Figure 3). Especially in cases in which the parent carbon molecule was aromatic or had aromatic or planar functional groups, the lowest energy geometry of each of the silicon analogues was not planar. A planar “silicon-based peptide bond” does not exist in nature, but scientists have engineered synthetic molecules called silicon-containing amino acids and peptides or used silicon compounds as catalysts to form peptide bonds. (Figure 4) depicts a graph of the minimized energies of the carbon parent molecules and the silicon analogues. On this graph are seven places where the minimized energy of the silicon analogue is larger than that of its carbon counterpart.

Figure 4: Minimized Energy Comparison Between Carbon and Silicon Analogues, (Kj/mole).

(Table 2) emphasizes the large, minimized energy difference between these seven silicon analogues and the parent carbon molecule. In the most extreme case, in which Si was substituted for C in Fe⁺²-protoporphyrin IX, found in heme proteins, the Si PPIX conformer had a minimized energy of 11,209.94 kJ/mole compared to that of the C PPIX conformer with a calculated minimized energy of 5,726.124 kJ/mole. (Figures 1 and 2) depict the dramatic differences in the geometry of the C-PPIX and the Si-PPIX. Just as silabenzene has been predicted to have a non-planar chair geometry see (Figure 5) below, we observed the same non-planarity in the porphyrin analogues (Molecules 10 and 12) as well as in other molecules studied that required a ring structure or planar geometry.

Figure 5: Comparison of aromaticity in nonplanar silabenzene (top) and planar benzene (bottom) [8].

Based upon our current studies presented herein, we propose the inability of Si to form strong p(π)-p(π) orbital overlap compared to that of carbon is one of the many contributing reasons silicon is unable to substitute for carbon in some important biomolecules. The ability to form strong p(π)-p(π) bonds is essential for the creation of multiple bonds in planar geometries that are structurally and mechanistically required in biological systems such as heme proteins, DNA bases, and peptide bonds. A comparison of p(π)-p(π) bond overlap in carbon and silicon is explained below.