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Solution acidity measured by pH is an important environmental factor that affects protein structure. It influences protonation state of protein residues, which in turn may be coupled to protein conformational changes, unfolding, and ligand binding. It remains difficult to compute and measure pK of individual residues, as well as to relate them to pH-dependent protein transitions. This paper presents a hierarchical approach to compute pK of individual protonatable residues, specifically histidines, coupled with underlying structural changes of a protein. A fast and efficient free energy perturbation (FEP) algorithm has been also developed utilizing a fast implementation of standard molecular dynamics (MD) algorithms. Specifically, a CUDA version of AMBER MD engine is used in this paper. Eight histidine pKs are computed in a diverse set of pH stable proteins to demonstrate the proposed approach's utility and assess the predictive quality of the AMBER FF99SB force-field. A reference molecule is carefully selected and tested for convergence. A hierarchical approach is used to model pKas of the six histidine residues of the Diphtheria Toxin Translocation domain (DTT), which exhibits a diverse ensemble of individual conformations and pH-dependent unfolding. The hierarchical approach consists of first sampling equilibrium conformational ensembles of a protein with protonated and neutral histidine residues via long equilibrium MD simulations [Flores-Canales, et al., bioRxiv, 2019, 572040]. A clustering method is then used to identify sampled protein conformations, and pKs of histidines in each protein conformation are computed. Finally, an ensemble averaging formalism is developed to compute a weighted average histidine pKs. These can be compared with an apparent experimentally measured pK of the DTT protein, and thus allows us to propose a mechanism of pH-dependent unfolding of the DTT protein.
This article was published in the following journal.
Name: The journal of physical chemistry. B
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An enzyme that catalyzes the first step of histidine catabolism, forming UROCANIC ACID and AMMONIA from HISTIDINE. Deficiency of this enzyme is associated with elevated levels of serum histidine and is called histidinemia (AMINO ACID METABOLISM, INBORN ERRORS).
A member of the transferase superfamily of proteins. In the activated state, protein-histidine kinase autophosphorylates at a histidine residue, subsequently transferring high-energy phosphoryl groups to an aspartate residue of the response-regulator domain, which results in a conformational shift in the effector domain. Histidine kinases mediate signal transduction in a wide range of processes involving cellular adaptation to environmental stress.
An enzyme that activates histidine with its specific transfer RNA. EC 126.96.36.199.
An enzyme that catalyzes the decarboxylation of histidine to histamine and carbon dioxide. It requires pyridoxal phosphate in animal tissues, but not in microorganisms. EC 188.8.131.52.
The penultimate step in the pathway of histidine biosynthesis. Oxidation of the alcohol group on the side chain gives the acid group forming histidine. Histidinol has also been used as an inhibitor of protein synthesis.
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