Tautomeric populations of the charged species of 1,12-diamino-3,6,9-triazadodecane (SpmTrien) studied with computer simulations and cluster expansions

Abstract

Correct net charge and protonation pattern in the polyamine backbone is one of the major factors that define the interactions of this class of compounds. 1,12‐diamino‐3,6,9‐triazadodecane (SpmTrien) is a isosteric charge deficient analogue of naturally occurring spermine (Spm) with different biological features. The tautomeric populations of each SpmTrien charge state were estimated with computer simulations, molecular dynamics (MD) and quantum mechanical calculations, and cluster expansions separately. In the computer simulations, tautomeric populations of each charge state were obtained by constrained least‐squares fitting the theoretically calculated (GIAO B3LYP/6‐311 + G**) 15 N NMR chemical shieldings of SpmTrien tautomers to the experimentally measured chemical shifts. Theoretical chemical shieldings were calculated for water complexes of SpmTrien obtained from MD simulations in explicit water. Both methods gave highly similar realistic results. SpmTrien has many major populations of tautomers at biologically relevant charge states of three (+3) and four (+4) thus enabling a large variety of structures for specific ionic interactions. Copyright © 2013 John Wiley & Sons, Ltd.

Structural-topological preferences and protonation sequence of aliphatic polyamines: a theoretical case study of tetramine trien

“…Also, one must realize that the obtained 40:60 ratio must not be taken literally as it must depend on a solvation model as well as level of theory used (we found e.g., 1% and 54% of HL p from modelling at HF and B97D level of theory, respectively) and, unfortunately, there is no easy way to rigorously verify any theoretical model experimentally. In support of this, Weisell et al [44] found, from QM-modelling of pentamine 1,12-diamino-3,6,9-triazadodecane (SpmTrien) involving explicit water molecules, that 91% (HL p ) and 9% (HL s ) is formed with short chain being protonated preferentially (66% short and 25% long chain for the HL p form) which clearly contradicts all earlier as well recent studies whereas from the CEA of NMR data they obtained 94% (HL p ) and 6% (HL s ) with long chain, as expected, being protonated preferentially, ~84%. Moreover, note that their findings, in general, are not in agreement with other studies as they predicted a very small fraction of HL s whereas this tautomer was found to be significant in many polyamines and even dominating, e.g., in spermine [5,8,41].…”

“…To test this, explicit water molecules in computational modelling must be used. Even though this must be seen as extremely time-demanding modelling, we decided to embark on this project because (i) we can make use of an effective conformational search protocol developed and tested here as well as (ii) data generated at the B3LYP level were found here to be sufficient for the purpose of the study (the same level of theory was also used recently in modelling of SpmTrien [44]. Focusing now on analysis of d(H,H), we found the following:…”

The intrinsic view of ionization equilibria of polyprotic molecules

“…23,24 This approach was refined to treat ionization of proteins and smaller molecules 18,25,26 and currently enjoys rapidly growing interest. 3,21,[27][28][29][30] The intrinsic description will be presented with examples of increasing complexity, thereby highlighting various strategies to extract the relevant parameters. We address the notion of group transferability, then the central idea of cluster expansion of the free energy, and finally molecular symmetries and homologous series.…”