Interaction of heteroboranes with biomolecules Part 2. The effect of various metal vertices and exo-substitutions

Abstract

Icosahedral heteroboranes and especially metallacarboranes, which have recently been shown to act as potent HIV-1 protease inhibitors, are a unique class of chemical compounds with unusual properties, one of which is the formation of dihydrogen bonds with biomolecules. In this study, we investigate the effect of various metal vertices and exo-substitutions on several series of heteroboranes, including 11-vertex carborane cages [nido-7,8-C₂B₉H_n]ⁿ⁻¹³ (n = 11,12,13), closo-1-SB₁₁H₁₁, closo-1-NB₁₁H₁₂, metal bis(dicarbollides) [3,3′-M (1,2-C₂B₉H₁₁)₂]ⁿ (M/n = Fe/2−, Co/1−, Ni/0) and fluoro (F), amino (NH₂) and hydroxo (OH) derivatives of the metal bis(dicarbollides). Besides the properties of isolated systems (geometries, electronic properties and hydration), we study their interactions with a tetrapeptide, which models their biomolecular partner. Calculations have confirmed that the extra hydrogen in [nido-7,8-C₂B₉H₁₂]⁻ forms a bridge, which fluctuates between two stationary states. Using RESP-derived charges, it was ascertained that the negative charge of heteroboranes is located mainly on boron-bound hydrogens. An increase of the negative total charge (from 0 to −1 or −2) of heteroboranes yields an increase in the stabilisation energies of heteroborane⋯peptide complexes and also a substantial increase in the hydration free energies of heteroboranes. Compared to the substitutions of metal vertices, the exo-substitutions of metallacarboranes cause a larger increase in stabilisation energies and a smaller increase in desolvation penalties. These two terms, stabilisation energies and desolvation penalties, contribute in opposite directions to the total heteroborane–biomolecule binding energy and must both be taken into account when designing new HIV-1 protease inhibitors.