Gate-based quantum computing for protein design.

Protein design is a technique to engineer proteins by permuting amino acids in the sequence to obtain novel functionalities. However, exploring all possible combinations of amino acids is generally impossible due to the exponential growth of possibilities with the number of designable sites. The present work introduces circuits implementing a pure quantum approach, Grover's algorithm, to solve protein design problems. Our algorithms can adjust to implement any custom pair-wise energy tables and protein structure models. Moreover, the algorithm's oracle is designed to consist of only adder functions. Quantum computer simulators validate the practicality of our circuits, containing up to 234 qubits. However, a smaller circuit is implemented on real quantum devices. Our results show that using [Formula: see text] iterations, the circuits find the correct results among all N possibilities, providing the expected quadratic speed up of Grover's algorithm over classical methods (i.e., [Formula: see text]).

Characterization of adjacent charged residues near the agonist binding site of the nematode UNC-49 GABA receptor.

The UNC-49 receptor is a Cys-loop GABA receptor that is unique to the nematode phylum. The receptor differs from mammalian GABA receptors both in amino acid sequence and pharmacology which highlights its potential as a novel anthelmintic target. Sequence differences within and near the various ligand-binding loops of the nematode receptor suggest that there could be structural differences compared to mammalian receptors that result in different pharmacological and functional features. Here we investigated three residues in the UNC-49 receptor from the parasitic nematode Haemonchus contortus: K181, E183, and T230. Analysis of these residues was conducted via site-directed mutagenesis, electrophysiology, MD simulations, and mutant cycling analysis. In the UNC-49 receptor, E183 lies in close proximity to K181 where together they appear to play a role in GABA sensitivity and pharmacology, possibly interacting via an ionic bond. While the introduction of single alanine residues at each position separately had a negative impact on GABA EC50, the double alanine mutant (K181A/E183A) exhibited wildtype-level GABA EC50 and some differences in pharmacology. Overall, this study has revealed a potentially novel role for these two residues in nematode UNC-49 GABA receptors that could aid in understanding their function.

Using geometric criteria to study helix-like structures produced in molecular dynamics simulations of single amylose chains in water.

Amylose is a linear polymer chain of α-d-glucose units connected through α(1 → 4) glycosidic bonds. Experimental studies show that in non-polar solvents, single amylose chains form helical structures containing precise H-bond patterns. However, both experimental and computational studies indicate that these perfectly H-bonded helices are not stable in pure water. Nevertheless, amylose chains are observed to form helix-like structures in molecular dynamics (MD) simulations that exhibit imperfect H-bond patterns. In this paper, we study the structure of amylose chains in water using MD simulations to identify and characterize these "imperfect" helical structures. To this end we devise geometry-based criteria to define imperfect helical structures in amylose chains. Using this approach, the propensity of amylose chains to form these structures is quantified as a function of chain length and solvent temperature. This analysis also uncovers both short and long time helix-breaking mechanisms such as band-flips and kinks in the chain. This geometric approach to defining imperfect helices thus allows us to give new insight into the secondary structure of single amylose chains in spite of imperfect H-bond patterns.

Two-dimensional 67Zn HYSCORE spectroscopy reveals that a Zn-bacteriochlorophyll aP' dimer is the primary donor (P840) in the type-1 reaction centers of Chloracidobacterium thermophilum.

Chloracidobacterium (C.) thermophilum is a microaerophilic, chlorophototrophic species in the phylum Acidobacteria that uses homodimeric type-1 reaction centers (RC) to convert light energy into chemical energy using (bacterio)chlorophyll ((B)Chl) cofactors. Pigment analyses show that these RCs contain BChl aP, Chl aPD, and Zn2+-BChl aP' in the approximate ratio 7.1 : 5.4 : 1. However, the functional roles of these three different Chl species are not yet fully understood. It was recently demonstrated that Chl aPD is the primary electron acceptor. Because Zn2+-(B)Chl aP' is present at low abundance, it was suggested that the primary electron donor might be a dimer of Zn2+-BChl aP' molecules. In this study, we utilize isotopic enrichment and high-resolution two-dimensional (2D) 14N and 67Zn hyperfine sublevel correlation (HYSCORE) spectroscopy to demonstrate that the primary donor cation, P840+, in the C. thermophilum RC is indeed a Zn2+-BChl aP' dimer. Density functional theory (DFT) calculations and the measured electron-nuclear hyperfine parameters of P840+ indicate that the electron spin density on P840+ is distributed nearly symmetrically over two Zn2+-(B)Chl aP' molecules as expected in a homodimeric RC. To our knowledge this is the only example of a photochemical RC in which the Chl molecules of the primary donor are metallated differently than those of the antenna.

All-Atom Molecular Dynamics Simulations of Dimeric Lung Surfactant Protein B in Lipid Multilayers.

Although lung surfactant protein B (SP-B) is an essential protein that plays a crucial role in breathing, the details of its structure and mechanism are not well understood. SP-B forms covalent homodimers, and in this work we use all-atom molecular dynamics simulations to study dimeric SP-B's structure and its behavior in promoting lipid structural transitions. Four initial system configurations were constructed based on current knowledge of SP-B's structure and mechanism, and the protein maintained a helicity consistent with experiment in all systems. Several SP-B-induced lipid reorganization behaviors were observed, and regions of the protein particularly important for these activities included SP-B's "central loop" and "hinge" regions. SP-B dimers with one subunit initially positioned in each of two adjacent bilayers appeared to promote close contact between two bilayers. When both subunits were initially positioned in the same bilayer, SP-B induced the formation of a defect in the bilayer, with water penetrating into the centre of the bilayer. Similarly, dimeric SP-B showed a propensity to interact with preformed interpores in the bilayer. SP-B dimers also promoted bilayer thinning and creasing. This work fleshes out the atomistic details of the dimeric SP-B structures and SP-B/lipid interactions that underlie SP-B's essential functions.

A mutational and molecular dynamics study of the cys-loop GABA receptor Hco-UNC-49 from Haemonchus contortus: Agonist recognition in the nematode GABA receptor family.

The UNC-49 receptor is a unique nematode γ-aminobutyric acid (GABA)-gated chloride channel that may prove to be a novel target for the development of nematocides. Here we have characterized various charged amino acid residues in and near the agonist binding site of the UNC-49 receptor from the parasitic nematode Haemonchus contorts. Utilizing the Caenorhabditis elegans GluCl crystal structure as a template, a model was generated and various charged residues [D83 (loop D), E131 (loop A), H137 (pre-loop E), R159 (Loop E), E185 (Loop B) and R241 (Loop C)] were investigated based on their location and conservation. These residues may contribute to structure, function, and molecular interactions with agonists. It was found that all residues chosen were important for receptor function to varying degrees. Results of the mutational analysis and molecular simulations suggest that R159 may be interacting with D83 by an ionic interaction that may be crucial for general GABA receptor function. We have used the results from this study as well as knowledge of residues involved in GABA receptor binding to identify sequence patterns that may assist in understanding the function of lesser known GABA receptor subunits from parasitic nematodes.

All-atom molecular dynamics simulations of lung surfactant protein B: Structural features of SP-B promote lipid reorganization.

Lung surfactant protein B (SP-B), a 79 residue, hydrophobic protein from the saposin superfamily, plays an essential role in breathing. Because of the extreme hydrophobicity of SP-B, the experimental structure of this protein has not yet been determined. Here, we run all-atom molecular dynamics simulations using the OPLS-AA force field in GROMACS to study SP-B's structure and mechanisms for promoting lipid reorganization. Firstly, we find that the final structures indicate the need for some fine-tuning of the homology-based secondary structure predictions. Secondly, we find energetically feasible structures 1) with SP-B's helices in the plane of the bilayer, 2) with SP-B's helices inclined with respect to the bilayer, and 3) with SP-B in a closed structure interacting peripherally with the bilayer. Interestingly, SP-B structures that were bent at the hinge region between the pairs of helices promoted and/or stabilized defects in the lipid bilayer. Finally, particular salt bridge patterns and structural plasticity in the central loop and adjacent region of SP-B appeared to be involved in SP-B's lipid reorganization abilities.

Molecular dynamics simulations of histidine-containing cod antimicrobial peptide paralogs in self-assembled bilayers.

Gaduscidin-1 and -2 (GAD-1 and GAD-2) are antimicrobial peptides (AMPs) that contain several histidine residues and are thus expected to exhibit pH-dependent activity. In order to help elucidate their mechanism of membrane disruption, we have performed molecular dynamics simulations with the peptides in both histidine-charged and histidine-neutral forms, along with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid molecules. The simulations employed GROMACS software and an OPLS-AA force field. Initially, the peptide and lipids were placed randomly in the simulation box and then were allowed to self-assemble. The results demonstrated a marked preference for the regions of the peptides that contain sequential pairs of histidine residues to associate closely with bilayer pores. This preference is observed even when the histidines are in their uncharged form. It appears that the relative compactness and rigidity of histidine pairs require the more aqueous and disordered environment of the pores to satisfy hydrophilic interactions. The final peptide structures exhibited a wide variety of structures and topologies, with the most helical structures positioning most parallel to the bilayer surface and the less ordered structures interacting more closely with the pore. Thus, the results give atomistic insight into those models of AMP mechanism that promote the importance of structural heterogeneity and imperfect amphipathicity to AMP activity and selectivity.