In addition, the main apparent conformational change of the DNA binding domain induced by effector binding is the variability of the separation between DNA binding motifs (h2 h3 and h2' h3'), which is shortened from 34.9 Å to 30.1 Å upon the inducer binding, while increased from about 34 Å to 39 50 Å in other TetR members identified to date [5], [6], [8], [11], [18], [19].
The electrostatic interaction between the applied electric field and the positively charged lysine side chains, whose amino groups were fully protonated, is proposed to be the main driving force for these switchable conformational changes.
Importantly, these results in no way alter the main conclusions regarding the nucleotide-driven conformational changes in the BSE reported by Chappie et al. Methods and supplemental Figure S1.
Various mechanisms have been proposed for inhibition of transporters by excipients, but the main concept behind inhibition is membrane fluidization-induced conformational changes and cholesterol depletion.
The binding site is pre-existing, and efficient docking of the compounds does not require significant conformational changes in side-chain or main-chain atoms.
In particular, the 280s loop (residues 282 287) shifts 0.4 4.3 Å (main-chain atoms) to accommodate the phosphoramidate, but these conformational changes do not lead to increased contacts between the inhibitor and the protein that would improve ligand binding.
Local conformational changes induced by substrate binding are widely considered as the main mechanism to drive the functional cycle of a transporter; in addition, reducing the energy barrier of the transition state has also been proposed to drive the transporter.
The main weaknesses of these methods are that they usually neglect factors such as conformational changes upon binding, allosteric regulation, and solvent and co-factor effects, which may all contribute to the binding strength.
Two main assumptions are imposed in our methodology: first, the subunits do not undergo significant conformational changes in forming different complexes, and second the arrangements of subunits in the different oligomers are consistent between sub-complexes.
Two main sensing mechanisms are used for the detection of DNA-related events, such as hybridisation, mismatch, single nucleotide polymorphism (SNP, SNPP genotyping, conformational changes, and cleavage of the nucleic acids.
