Protein Families Contain Proteins With Identical Primary, Secondary, and Tertiary Structures.

Protein Third Structure

Protein tertiary construction prediction is a research field which aims to create models and software tools able to predict the three-dimensional shape of protein molecules past describing the spatial disposition of each of its atoms starting from the sequence of its amino acids.

From: Encyclopedia of Bioinformatics and Computational Biological science , 2019

Membrane Proteins

Philip L. Yeagle , in The Membranes of Cells (3rd Edition), 2016

10.vi Tertiary Structure of Membrane Proteins

Membrane protein third construction is different from soluble poly peptide tertiary structure primarily in the structural requirements imposed past the incorporation of these proteins in the membrane. Therefore peripheral membrane poly peptide tertiary structure does not differ significantly from soluble protein tertiary construction. However differences are apparent in the integral membrane proteins.

Integral membrane proteins submerge a portion of their mass into the hydrophobic interior of the membrane. As has already been discussed, this imposes strict requirements on the structure of the protein. To meet these requirements, integral membrane proteins are divided into domains. In general these will be extramembraneous domains and transmembrane domains. The extramembraneous domains have structural properties like to water-soluble proteins. The transmembrane domains take hydrophobic surfaces facing the hydrophobic interior of the membrane. The three-dimensional structures of membrane proteins visually present a articulate distinction in many cases for this domain structure. A number of examples are represented in the figures in several chapters, including this one in Fig. 10.xiii.

Figure 10.13. Three-dimensional structure of human estrone sulfatase from X-ray crystallography. The model is produced from PDB 1P49.

What domains support functional sites for these membrane proteins? Much of the enzymology is catalyzed by active sites that are found on the extramembraneous domains of the protein. For case, the ATP hydrolysis active site on the Na⁺ K⁺ ATPase is in an extramembraneous domain (meet affiliate: Membrane Transport). The sites that catalyze phosphorylation, including autophosphorylation, on the insulin receptor are located in an extramembraneous domain (see affiliate: Membrane Receptors). Other functional activity can likewise be constitute in extramembraneous domains: the fusion peptide of the influenza viral fusion protein is in the extramembraneous domain (run into chapter: Membrane Fusion).

Transmembrane domains also limited biological role. For example, the active site of UbiA, a prenyl transferase, is located in the transmembrane domain. ²⁶ Fig. ten.14 shows the structure. Rhodopsin binds the ligand that is responsive to low-cal, xi-cis retinal, in a pocket in the transmembrane domain (see chapter: Membrane Receptors). The functionality of some porins, namely transport, is expressed by a transmembrane domain (see chapter: Membrane Transport).

Figure ten.14. The three-dimensional structure of a prenyl transferase (UbiA), showing the location of the agile site (molecule at van der Waals radii), which is within the membrane (location of the phospholipid bilayer is shown schematically). The figure of the protein is produced from PDB: 4OD5 and the data were obtained past X-ray crystallography.

These features of domain structure in integral membrane proteins are being discussed hither in the context of the better-known principal, secondary, and tertiary structure of soluble proteins. More details of domains in integral membrane proteins will be explored afterward.

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Computational Methods in Molecular Biological science

David Jones , in New Comprehensive Biochemistry, 1998

1 Introduction

The prediction of protein third structure from sequence may exist expressed symbolically by expressing the folding process equally a mathematical part

$C=F\left(\mathrm{Due\; south}\right)$

where

$S=\left[s_1,s_{\mathrm{two}},\dots ,s_n\right],C=\left[{\theta }_1,{\theta }_2,\dots ,{\theta }_{3n-2}\right],s\in \left\{\text{Ala, Arg,}\dots \text{,Val}\right\}.$

In this case the main chain conformation of the poly peptide concatenation S is represented as a vector of main concatenation torsion angles C , with the concatenation itself beingness defined equally a vector of elements respective to members of the fix of 20 standard amino acids. The folding process is therefore defined as a function which takes an amino acid sequence and computes from it a sequence of primary chain torsion angles. The choice of representation of the folded concatenation conformation in torsion space is arbitrary, and the problem tin only as readily exist expressed in terms of relative orthogonal 3D coordinates, or with some indeterminacy in chirality, interatomic distances.

The protein folding trouble can thus exist considered a search for the folding function F. Information technology is likely, yet, that no simple representation of the folding function exists, and that even if the function exists in whatsoever grade whatsoever, the only device capable of performing the required office evaluation is the poly peptide chain itself. Conceptually, the simplest manner to arrange for a protein sequence to code for its own native 3D structure is to arrange for the native construction to exist the global minimum of the protein chain's free energy. The folding process is therefore transformed into an energy function minimization process, where the energy function could take as input the protein sequence vector S , and the vector of torsion angles C . Given a particular sequence Southward , the folding procedure is therefore transformed into a search through the set of all corresponding vectors of torsion angles C . for the minimum of an energy role E, where E is divers thus:

$\mathrm{East}\left(S,C_{\text{native}}\right)<\mathrm{East}\left(S,C_{\text{non-native}}\right).$

The exact form of this energy function is as yet unknown, but information technology is reasonable to presume that information technology would incorporate terms pertaining to the types of interactions observed in protein structures, such equally hydrogen bonding and van der Waals effects. The conceptual simplicity of this model for poly peptide folding stimulated much research into ab initio tertiary structure prediction. A successful ab initio approach necessitates the solution of two problems. The first problem to solve is to find a potential function for which the above inequality at least generally holds. The second problem is to construct an algorithm capable of finding the global minimum of this function. To engagement, these problems remain substantially unsolved, though some progress has been made, particularly with the construction of efficient minimization algorithms.

Information technology is unlikely that proteins actually locate the global minimum of a gratuitous energy function in gild to fold into their native conformation. The case confronting proteins searching conformational space for the global minimum of gratis energy was argued by Levinthal [1]. The Levinthal paradox, as it is now known, tin be demonstrated adequately hands. If we consider a protein chain of Northward residues, we can approximate the size of its conformational space equally roughly 10 ^North states. This assumes that the main chain conformation of a protein may be adequately represented by a suitable choice from but x master chain torsion bending triplets for each balance. In fact, Rooman et al. [2] have shown that just 7 states are sufficient. This of course neglects the additional conformational infinite provided by the side chain torsion angles, but is a reasonable rough judge, albeit an underestimate. The paradox comes from estimating the time required for a protein chain to search its conformational space for the global energy minimum. Taking a typical poly peptide chain of length 100 residues, it is clear that no physically achievable search charge per unit would enable this chain to complete its folding process. Even if the atoms in the chain were able to movement at the speed of calorie-free, it would take the concatenation around 10⁸² seconds to search the entire conformational space, which compares rather unfavorably to the estimated age of the Universe (10¹⁷ seconds).

Clearly proteins exercise not fold by searching their entire conformational space. In that location are many means of explaining away Levinthal'south paradox. A highly plausible mechanism for protein folding is that of encoding a folding pathway in the protein sequence. Despite the fact that chains of significant length cannot notice their global energy minimum, short chain segments (five–7 residues) could quite easily locate their global energy minimum inside the average lifetime of a poly peptide, and it is therefore plausible that the location of the native fold is driven by the folding of such short fragments [3]. Levinthal's paradox is but a paradox if the costless energy function forms a highly convoluted free energy surface, with no obvious downhill paths leading to the global minimum. The folding of a curt fragment tin exist envisaged as the traversal of a small downhill segment of the free energy surface, and if these paths somewhen converge on the global energy minimum, then the protein is provided with a uncomplicated ways of rapidly locating its native fold.

One subtle point to brand almost the relationship betwixt the minimization of a protein's complimentary energy and protein folding is that the native conformation need non correspond to the global minimum of free energy. I possibility is that the folding pathways initially locate a local minimum, just a local minimum which provides stability for the average lifetime of the protein. In this case, the protein in question would e'er be observed with a free energy slightly higher than the global minimum in vivo, but would eventually locate its global minimum if isolated and left long plenty in vitro – though the location of the global minimum could take many years. Thus, a biologically active protein could in fact be in a metastable country, rather than a stable one.

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Ab initio Protein Construction Prediction

Rahul Kaushik , ... B. Jayaram , in Encyclopedia of Bioinformatics and Computational Biology, 2019

ASTRO-FOLD

ASTRO-FOLD performs ab initio protein tertiary-construction prediction based on a combinatorial and global optimization framework (Klepeis and Floudas, 2003). The initial version of ASTRO-FOLD implemented a hierarchical method that integrated an all-atom free energy function, global optimization algorithm, conformational space annealing, and MD simulations in dihedral angle conformational space. More recently, an updated version of ASTRO-FOLD has been released (christened ASTRO-FOLD 2.0) that predicts the secondary structure of a target protein using diverse statistical potentials, followed by contact prediction, and loop prediction (Subramani et al., 2012). These predictions are used for deriving various restraints, such as dihedral angle and C_α–C_α altitude restraints. The restraints are used for further conformational sampling using a combinatorial and global optimization algorithm. A simplified workflow of ASTRO-FOLD 2.0 is shown in Fig. 5.

Fig. five. A workflow of ASTRO-FOLD 2.0 for ab initio protein structure prediction.

Based on methodology explained in Subramani, A., Wei, Y., &amp; Floudas, C.A., 2012. ASTRO-FOLD 2.0: An enhanced framework for protein structure prediction. AIChE Journal, 58(5), 1619–1637.

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Algorithms for Structure Comparison and Analysis: Homology Modelling of Proteins

Marco Wiltgen , in Encyclopedia of Bioinformatics and Computational Biology, 2019

Abstruse

This article presents the basic principles of protein tertiary construction prediction by homology modelling, which is a knowledge-based prediction based on parameters extracted from existing structures that predicts a new construction from its sequence. The necessary condition for homology modelling is a sufficient similarity between the query and template protein sequences which is fulfilled for proteins from the same family unit. Today, for a lot of protein families, at least one member with a known structure is available which augments the applicability of homology modelling. Because many proteins are of immediate clinical importance, the determination of their structures plays an of import role in medicine.

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Hemoglobin metabolism

Catherine N. Otto , in Rodak's Hematology (Sixth Edition), 2020

Complete hemoglobin molecule

The hemoglobin molecule can be described past its principal, secondary, tertiary, and quaternary protein structures. The main construction refers to the amino acrid sequence of the polypeptide bondage. The secondary construction refers to chain arrangements in helices and nonhelices. The tertiary structure refers to the arrangement of the helices into a pretzel-like configuration.

Globin chains loop to form a crack pocket for heme. Each chain contains a heme grouping that is suspended between the East and F helices of the polypeptide concatenation (Figure seven.3). ^{2 , three} The fe cantlet at the center of the protoporphyrin IX band of heme is positioned between two histidine radicals, forming a proximal histidine bond within F8 and, through the linked oxygen, a close association with the distal histidine balance in E7. ³ Globin concatenation amino acids in the crack are hydrophobic, whereas amino acids on the outside are hydrophilic, which renders the molecule water soluble. This organization also helps iron remain in its divalent ferrous form regardless of whether information technology is oxygenated (carrying an oxygen molecule) or deoxygenated (not conveying an oxygen molecule).

The 4th structure of hemoglobin, also called a tetramer, describes the complete hemoglobin molecule. The complete hemoglobin molecule is spherical, has four heme groups attached to iv polypeptide bondage, and may carry up to four molecules of oxygen (Effigy 7.4). The predominant adult hemoglobin, Hb A, is composed of 2 α-globin chains and two β-globin chains. Potent α_i-β_one and α_two-β_ii bonds concur the dimers in a stable form. The α₁-β₂ and α_two-β_i bonds are important for the stability of the quaternary structure in the oxygenated and deoxygenated forms (Figure 7.i). ^{1 , 2}

A pocket-sized pct of Hb A is glycated. Glycation is a posttranslational modification formed by the nonenzymatic binding of diverse sugars to globin chain amino groups over the life span of the RBC. The about characterized of the glycated hemoglobins is Hb A_1c, in which glucose attaches to the Northward-terminal valine of the β chain. ⁱ Ordinarily, most iv% to vi% of Hb A circulates in the A_1c form. In uncontrolled diabetes mellitus, the amount of A_1c is increased proportionally to the mean claret glucose level over the preceding 2 to 3 months.

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Protein Structure Analysis

M. Michael Gromiha , in Protein Bioinformatics, 2010

3.12.four MATRAS

Kawabata and Nishikawa (2000) developed the plan, MATRAS, for comparing protein third structures using the Markov transition model of evolution. In this method, the similarity score between structures i and j has been defined every bit log P(j →i)/P(i),where P(j →i) is the probability that structure j changes to construction i during the evolutionary procedure, and P(i) is the probability that structure i appears by chance. MATRAS takes the PDB lawmaking or whatever file in the PDB format and sends the structure comparison results past e-mail. Information technology has several features that one tin can search the similar positions within a protein, between two proteins, and a poly peptide with several databases. Information technology is freely bachelor at http://biunit.aist-nara.ac.jp/matras/.

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Dancing Protein Clouds: Intrinsically Disordered Proteins in Health and Disease, Function B

Galina Due south. Nagibina , ... Bogdan Southward. Melnik , in Progress in Molecular Biology and Translational Science, 2020

four L1 protein study

To find disarming confirmation of correlation of high intrinsic disorder propensities with weakness of protein tertiary structure one must attempt to exclude all other factors affecting protein stability during introduction of cysteine bridges, such as structural features of the proteins and positions of amino acid residues specific for mutations.

The idea is that to correctly test our supposition, it is necessary to study ii proteins with identical 3-dimensional structures, simply quite different amino acrid sequences. Similar three-dimensional structure gives us the opportunity to introduce amino acid substitutions into similar regions of proteins with identical secondary construction. Dissimilar amino acrid sequences give unlike intrinsic disorder propensity values for structurally identical parts of the proteins. Hence, introduction of identical substitutions into similar structural motifs of proteins with various intrinsic disorder propensities allows us to exclude the effect of secondary construction context for the regions of introduced disulfide bonds.

Two ribosomal proteins L1 were called for this study, L1 from the halophilic archaeon Haloarcula marismortui (HmaL1) and L1 from the extremophilic bacterium Aquifex aeolicus (AaeL1). The 3-dimensional structure of AaeL1 is known from the experiments [35]; for HmaL1, a homology model was congenital [36]. Both proteins accept highly conservative three-dimensional structure specific for ribosome L1 proteins, which tin can be divided into two domains. The amino acid sequences of these proteins take sequence identity of but 33%. Hence, this pair of proteins satisfies our requirements: They are similar in structure, only quite different in sequence.

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Poly peptide and Peptide Delivery through Respiratory Pathway

Hemal Tandel , ... Ambikanandan Misra , in Challenges in Delivery of Therapeutic Genomics and Proteomics, 2011

9.3.4.one.3 Interfacial Backdrop

The presence of an air–h2o or solid–water interface disrupts the normal forces stabilizing protein secondary, tertiary, and quaternary structure in solution [8]. Partial unfolding occurs, which may so atomic number 82 to adsorption to the surface through interaction between hydrophobic amino acid residues and the surface, and electrostatic forces betwixt polar amino acid residues to charged surfaces. Thus, peptides and proteins are adsorbed quite readily to both nonpolar solid surfaces (such as polyperfluoroethylene and polystyrene) and to surfaces with ion-exchange properties (such every bit glass). These parameters must be considered during manufacturing, packaging, and storage of proteins and peptide formulations. Some proteins incorporate hydrophobic amino acids that form cylindrical sail similar structures that readily penetrate lipid membranes, which contributes to a high affinity of the protein for oil–h2o interfaces.

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Isotope Labeling of Biomolecules - Applications

Elyssia S. Gallagher , Jeffrey W. Hudgens , in Methods in Enzymology, 2016

2.iv Protein Construction

The exchange rate of a courage amide N–H is dependent on the primary, secondary, tertiary, and fourth poly peptide structure. For an unfolded protein or peptide, the identities of the neighboring amino acids affect the magnitude of yard _ch. Englander (Bai et al., 1993; Connelly, Bai, Jeng, & Englander, 1993; Englander, 2015) provides tables that can predict k _ch for unfolded peptides based on pH, temperature, and neighboring amino acids.

The Linderstrøm-Lang model of hydrogen exchange describes exchange by localized unfolding. Amides can reside in either exchange-incompetent (N-H_closed) or commutation-competent (N-H_open) states (Hvidt & Linderstrøm-Lang, 1954). Any hydrogen-bonded proton is exchange-incompetent because it is sterically inaccessible to exchange (Englander, Mayne, Bai, & Sosnick, 1997). Mostly, secondary structural features (e.thousand., α-helices, β-sheets) in a folded protein are comprised of amides residing in commutation-incompetent states since they are stabilized through intramolecular hydrogen bonds. The Linderstrøm-Lang model posits that an amide North–H group becomes exchange-competent through unspecified transient events. The Linderstrøm-Lang model is divers kinetically by the structural opening and reclosing rates, chiliad _op and k _cl, of an amide:

(2) $\mathrm{Northward}–{\mathrm{H}}_{\mathrm{airtight}}\underset{{\mathrm{1000}}_{\mathrm{cl}}}{\overset{k_{\mathrm{op}}}{\rightleftarrows }}\mathrm{N}–{\mathrm{H}}_{\mathrm{open}}\underset{{\mathrm{D}}_2\mathrm{O}}{\overset{k_{\mathrm{c}\mathrm{h}}}{\to }}\mathrm{exchanged}$

The substitution process proceeds during transient, exchange-competent intervals when the hydrogen bond donor and acceptor are not bound (Northward-H_open) and are solvent accessible. The Linderstrøm-Lang model attributes the variation of thou _op and k _cl to the presence and absence of secondary construction, and these dynamical variables connect poly peptide structure to thermodynamic backdrop (Englander et al., 1997; Hvidt & Linderstrøm-Lang, 1954; Hvidt & Nielsen, 1966). Protection confronting amide Northward–H exchange, conferred by secondary structure through variation of k _op and chiliad _cl, tin can reduce the H/D commutation rate at amide groups by as much every bit 10⁸ (Fleming & Rose, 2005; Skinner, Lim, Bédard, Blackness, & Englander, 2012).

When a hydrogen bond is broken, a kinetic contest ensues between the rates of chemical exchange, k _ch, and structural reclosing, k _cl (Baldwin, 2011; Englander & Kallenbach, 1984; Hvidt & Nielsen, 1966). Under about physiological conditions, reclosing is faster than chemical exchange (k _cl  ≫ chiliad _ch), requiring the same hydrogen bond to interruption multiple times before a successful commutation upshot. The hydrogen exchange rate and so depends on the fraction of time the exchange-competent (open) course exists and therefore the structural opening equilibrium constant (K _op). The kinetic expression for this EX2 status is written with a preequilibrium step:

(3) $k_{\mathrm{H}\mathrm{D}\mathrm{X}}=\frac{k_{\mathrm{op}}{k}_{\mathrm{c}\mathrm{h}}}{\left(k_{\mathrm{op}}+k_{\mathrm{c}\mathrm{h}}+k_{\mathrm{cl}}\right)}\approx K_{\mathrm{op}}{k}_{\mathrm{c}\mathrm{h}}$

where k _HDX is the observed exchange charge per unit. The equilibrium term, M _op, represents the fraction of time that the amide is exchange-competent. The approximation shown in Eq. (iii) holds for any pregnant level of structural protection (k _op/thousand _cl  ≈ K _op  <   one). The Gibb'due south energy alter, ${\Delta }_{\mathrm{op}}{G}^{°}$ , is the opening energy for exchange at amide Northward–H:

(4) ${\mathrm{\Delta }}_{\mathrm{op}}{\mathrm{Thousand}}^{\circ }=-RTln{K}_{\mathrm{op}}=-RTln\left(\frac{{\mathrm{1000}}_{\mathrm{op}}}{{\mathrm{thou}}_{\mathrm{cl}}}\right)$

As the chemical charge per unit is fabricated progressively faster, for example, by raising the pH, the amide substitution charge per unit will increase linearly with the solvent catalyst concentration in the EX2 range. Ultimately, when thousand _ch  > g _cl, the HX exchange charge per unit will reach the asymptotic EX1 limit at which the deuteration rate coefficient, yard _HDX, becomes

(v) $k_{\mathrm{H}\mathrm{D}\mathrm{X}}=g_{\mathrm{op}}$

EX1 beliefs tin be documented by its insensitivity to pH or by ascertainment of correlated D-uptake behavior, where multiple amides simultaneously exchange and showroom the same EX1 exchange rate (Englander, 2006).

Many studies have been devoted to determining how protein structure governs amide hydrogen exchange patterns. These studies have explored solvent and catalyst penetration models. Analysis of model-based expectations for hydrogen exchange indicate that local unfolding pathways manifest activation energies of East _a  =   lxx–145   kJ/mol and penetration mechanisms manifest East _a  >   165   kJ/mol (Englander & Kallenbach, 1984). Studies of poly peptide amide N–H exchange dynamics have successfully deemed for HDX-MS and HDX-NMR data with local unfolding and foldon models (Englander, Mayne, & Krishna, 2007; Hu et al., 2013; Krishna, Hoang, Lin, & Englander, 2004; Krishna, Maity, Rumbley, Lin, & Englander, 2006).

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Chemical and Biochemical Approaches for the Study of Coldhearted Role, Part A

Paul Hoerbelt , Boris D. Heifets , in Methods in Enzymology, 2018

three.i.1 Equipment

•

Computer with Deoxyribonucleic acid-editing software (eastward.1000., A Plasmid Editor [ApE], SnapGene, Deoxyribonucleic acid Strider).

•

Software for viewing receptor protein tertiary structure (e.g., Swiss-PdbViewer).

•

Polymerase chain reaction (PCR) car (i.e., thermal cycler).

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PCR tubes (200 or 50   μL volume).

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Small-scale-volume spectrophotometer (eastward.g., NanoDrop) and associated software.

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Electrophoresis equipment (including lane dividers/combs, power supply, and gel beds for agarose gels).

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Ultraviolet (UV) light source; both long- and short-wave if possible.

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Gel extraction kit for Deoxyribonucleic acid (e.thou., QIAquick or GeneJET).

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DNA purification kits for miniprep and maxiprep (from Qiagen, Thermo Fisher Scientific, or Zymo).

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T4 DNA ligation kit.

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Water or dry bath/heating block (for temperatures of 42°C or 55°C).

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Bacterial shaker.

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fourteen-mL civilisation tubes.

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100- to 250-mL Erlenmeyer flasks.

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Snap-peak and screw-acme ultracentrifuge tubes (1.5   mL).

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−   fourscore°C freezer.

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Autoclave.

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Refrigerated floor centrifuge (Sorvall or Beckmann) with large tubes and rotors for preparation of bacterial pellets and Deoxyribonucleic acid pellets.

•

Deoxyribonucleic acid SpeedVac.

•

Gel imager and computer.

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