Protein Dynamics and Substrate Protonation State Mediate the Catalytic Action of Trans-4-Hydroxy-L-Proline Dehydratase

10.26434/chemrxiv.14456562 ◽

2021 ◽

Author(s):

Zhongyue Yang ◽

Heather Kulik

Keyword(s):

Hydrophobic Interactions ◽

Multiple Time ◽

Protonation State ◽

Deprotonated Form ◽

Healthy Human ◽

Functional Feature ◽

Enzyme Active Site ◽

Time Dynamics ◽

Long Time ◽

Protein Environment

The enzyme trans-4-Hydroxy-L-proline (Hyp) dehydratase (HypD) is among the most abundant glycyl radical enzymes (GREs) in the healthy human gut microbiome and is considered a promising antibiotic target for the prominent antibiotic-resistant pathogen Clostridium difficile. Although an enzymatic mechanism has been proposed, the role of the greater HypD protein environment in mediating radical reactivity is not well understood. To fill this gap in understanding, we investigate HypD across multiple time- and length- scales using electronic structure modeling and classical molecular dynamics. We observe that the Hyp substrate protonation state significantly alters both its enzyme-free reactivity and its dynamics within the enzyme active site. Accurate coupled cluster modeling suggests the deprotonated form of Hyp to be the most reactive protonation state for C5–Hpro-S activation. In the protein environment, hydrophobic interactions modulate the positioning of Cys434 radical to enhance the reactivity of C5–Hpro-S abstraction. Long-time dynamics reveal that changing Hyp protonation states triggers the switching of a Leu643-gated water tunnel, a functional feature that has not yet been observed for members of the GRE superfamily.

Download Full-text

Catalytic center of cytochrome c oxidase: Effects of protein environment on pKa values of cub histidine ligands

Journal of the Serbian Chemical Society ◽

10.2298/jsc200720047p ◽

2020 ◽

Vol 85 (11) ◽

pp. 1429-1444

Author(s):

Dragan Popovic ◽

Ivana Djordjevic

Keyword(s):

Binuclear Complex ◽

Proton Pumping ◽

Charged State ◽

Protonation State ◽

Model Compounds ◽

Deprotonated Form ◽

Catalytic Center ◽

Pka Values ◽

Protein Environment

The molecular mechanism by which electron transfer (ET) is coupled to proton pumping in cytochrome oxidase is one of the main unsolved problems in biochemistry. Particularly, the nature and position of the proton-loading site is under dispute. The CuB complex has three ligated histidines, whereas only His290 and His291 are ionizable sites with the same pKa values in aqueous solution, but apparently quite different ones within the enzyme. Earlier, a model of proton pumping with the central role of His290 was proposed. Recent calculations indicate that the His291 ligand of the CuB center might play the role of the pumping element, since its protonation state depends on the oxidation state of the binuclear complex (BNC). The present electrostatic study was applied to assess the role of the protein environment on the acidity of the two histidines. Their pKa values and effects of different energy terms were evaluated to discover the nature of their diverse behavior in the enzyme. Here, a new set of pKa values for the non-standard model compounds within the BNC was applied. The enhanced results are compared with results of previous studies in the light of the plausible proton pumping mechanism. The obtained microscopic and apparent pKa values in the oxidized state of BNC are virtually the same, indicating that deprotonated form of His291 accounts for the large pKa increase of His290, since then both titratable sites on then CuB center cannot simultaneously be in the charged state. The present results support the underlined His291 pumping model.

Download Full-text

Long-time dynamics of a class of nonlocal extensible beams with time delay

Mathematics and Mechanics of Solids ◽

10.1177/10812865211019457 ◽

2021 ◽

pp. 108128652110194

Author(s):

Fengjuan Meng ◽

Cuncai Liu ◽

Chang Zhang

Keyword(s):

Time Delay ◽

Stability Property ◽

Beam Equation ◽

Exponential Attractors ◽

Time Dynamics ◽

Bounded Smooth Domain ◽

Finite Dimensional ◽

Long Time ◽

Bounded Smooth ◽

Long Time Dynamics

This work is devoted to the following nonlocal extensible beam equation with time delay: [Formula: see text] on a bounded smooth domain [Formula: see text]. The main purpose of this paper is to consider the long-time dynamics of the system. Under suitable assumptions, the quasi-stability property of the system is established, based on which the existence and regularity of a finite-dimensional compact global attractor are obtained. Moreover, the existence of exponential attractors is proved.

Download Full-text