Protein Structure Notes_Level 1_Medical Students

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Protein structure: Primary, Secondary and Tertiary

Thursday, 6th November 2008-11-06 Medical Students Level 2

By Dr. Judith N. Torimiro

1 Levels of protein structure

2 Structure of the amino acids

o 2.1 Primary structure of proteins

o 2.2 Secondary structure in proteins

o 2.3 The a-Helix

2.3.1 Typical -Helix

o 2.4 -sheets

o 2.5 Super-Secondary Structure

o 2.6 Tertiary Structure of Proteins

o 2.7 Quaternary Structure

3 Forces Controlling Protein Structure

o 3.1 Hydrogen Bonding

o 3.2 Hydrophobic Forces

o 3.3 Electrostatic Forces

o 3.4 van der Waals Forces

Proteinsare an important class of biological macromolecules present in all biological organisms, made up of such elements as carbon

,hydrogen

,

nitrogen

,phosphorus

,oxygen

, and sulfur. All proteins arepolymersofamino acids. The polymers, also known aspolypeptides consist of asequence of 20 different L--amino acids, also referred to as residues. For chains under 40 or 50 residues the termpeptideis frequently used

instead of protein. To be able to perform their biological function, proteins fold into one, or more, specific spatial conformations, driven by a

number of noncovalentinteractions such as hydrogen bonding

, ionic interactions, Van der Waals forces and hydrophobic packing. In order to

understand the functions of proteins at a molecular level, it is often necessary to determine the three dimensional structure of proteins. This is the
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topic of the scientific field ofstructural biology, that employs techniques such asX-ray crystallography orNMR spectroscopy, to determine the

structure of proteins.

Peptide: A molecule consisting of 2 or more amino acids. Peptides are smaller than proteins, which are also chains of amino acids. Molecules small enough to be synthesizedfrom the constituent amino acids are, by convention, called peptides rather than proteins. The dividing line is at about 50 amino acids. Depending on the number of amino

acids, peptides are called dipeptides, tripeptides, tetrapeptides, and so on.

A number of residues are necessary to perform a particularbiochemical function, and around 40-50 residues appears to be the lower limit for a

functionaldomain size. Protein sizes range from this lower limit to several thousand residues in multi-functional or structural proteins. However,

the current estimate for the average protein length is around 300 residues. Very large aggregates can be formed fromprotein subunits

, for

example many thousandactin molecules assemble into a microfilament.

The primary structure of peptides and proteins refers to the linear number and order of the amino acids present.

Levels of protein structure

Around 90% of the protein structures available in theProtein Data Bankhave been determined by X-ray crystallography. This method

allows one to measure the 3D density distribution of electrons in the protein (in the crystallized state) and thereby infer the 3D coordinates of all

the atoms to be determined to a certain resolution. Roughly 9% of the known protein structures have been obtained by Nuclear Magnetic

Resonance techniques, which can also be used to determine secondary structure

Biochemistry refers to four distinct aspects of a protein's structure:

Primary structure - the amino acid sequence of the peptide chains.

Secondary structure - highly regular sub-structures (alpha helix andstrands ofbeta sheet

) which are locally defined, meaning that there

can be many different secondary motifs present in one single protein molecule.

Tertiary structure - three-dimensional structure of a single protein molecule; a spatial arrangement of the secondary structures. It also

describes the completely folded and compacted polypeptide chain.

Quaternary structure - complex of several protein molecules or polypeptide chains, usually called protein subunits in this context,

which function as part of the larger assembly or protein complex.
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In addition to these levels of structure, a protein may shift between several similar structures in performing its biological function. In the context

of these functional rearrangements, these tertiary or quaternary structures are usually referred to as chemical conformation, and transitionsbetween them are called conformational changes.

The primary structure is held together bycovalent orpeptide bonds

, which are made during the process ofprotein biosynthesis or translation.

These peptide bonds provide rigidity to the protein. The two ends of the amino acid chain are referred to as the C-terminal end or carboxylterminus (C-terminus) and the N-terminal end or amino terminus (N-terminus) based on the nature of the free group on each extremity.

The various types of secondary structure are defined by theirpatterns of hydrogen bonds between the main-chain peptide groups. However, these

hydrogen bonds are generally not stable by themselves, since the water-amide hydrogen bond is generally more favorable than the amide-amide

hydrogen bond. Thus, secondary structure is stable only when the local concentration of water is sufficiently low, e.g., in the molten globule or

fully foldedstates.

Similarly, the formation of molten globules and tertiary structure is driven mainly by structurally non-specific interactions, such as the rough

propensities of the amino acids and hydrophobic interactions. However, the tertiary structure isfixedonly when the parts of a protein domain are

locked into place by structurallyspecific interactions, such as ionic interactions (salt bridges), hydrogen bonds and the tight packing of side

chains. The tertiary structure of extracellular proteins can also be stabilized by disulfide bonds

, which reduce the entropy of the unfolded state;disulfide bonds are extremely rare in cytosolic proteins, since the cytosol is generally a reducing environment.

Primary structure of proteins

The primary structure of peptides and proteins refers to the linear number and order of the amino acids present. The convention for the

designation of the order of amino acids is that theN-terminal end (i.e. the end bearing the residue with the free -amino group) is to the left (and

the number 1 amino acid) and the C-terminal end (i.e. the end with the residue containing a free -carboxyl group) is to the right.

The sequence of the different amino acids is called theprimary structure of the peptide or protein. Counting of residues always starts at the N-

terminal end (NH2-group), which is the end where the amino group is not involved in a peptide bond. The primary structure of a protein isdetermined by the gene corresponding to the protein. A specific sequence ofnucleotides in DNA is transcribed into mRNA

, which is read by the

ribosome in a process called translation. The sequence of a protein is unique to that protein, and defines the structure and function of the protein.

The sequence of a protein can be determined by methods such asEdman degradation ortandem mass spectrometry. Often however, it is read

directly from the sequence of the gene using thegenetic code. Post-transcriptional modifications such as disulfide formation, phosphorylations

and glycosylations are usually also considered a part of the primary structure, and cannot be read from the gene.
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Secondary structure in proteins

The ordered array of amino acids in a protein confer regular conformational forms upon that protein. These conformations constitute the

secondary structures of a protein. In general proteins fold into two broad classes of structure termed, globular proteins or fibrous proteins.

Globular proteins are compactly folded and coiled, whereas, fibrous proteins are more filamentous or elongated. It is the partial double-bond

character of the peptide bond that defines the conformations a polypeptide chain may assume. Within a single protein different regions of thepolypeptide chain may assume different conformations determined by the primary sequence of the amino acids.

By building models of peptides using known information about bond lengths and angles, the first elements of secondary structure, the alpha helix

and thebeta sheet

, were suggested in 1951 byLinus Pauling and coworkers.[1] Both the alpha helix and the beta-sheet represent a way of

saturating all the hydrogen bond donors and acceptors in the peptide backbone. These secondary structure elements only depend on propertiesthat all the residues have in common, explaining why they occur frequently in most proteins. Since then other elements of secondary structure

have been discovered such as various loops and other forms of helices. The part of the backbone that is not in a regular secondary structure is

said to be random coil.

The a-Helix

The -helix is a common secondary structure encountered in proteins of the globular class. The formation of the -helix is spontaneous and is

stabilized by H-bonding between amide nitrogens and carbonyl carbons of peptide bonds spaced four residues apart. This orientation of H-

bonding produces a helical coiling of the peptide backbone such that the R-groups lie on the exterior of the helix and perpendicular to its axis.

Typical -Helix

Not all amino acids favor the formation of the (-helix due to steric constraints of the R-groups). Amino acids such as (alanine, arspatate,

glutamate, isoleucine, leucine and methionine (A, D, E, I, L and M) favor the formation of -helices, whereas, glycine and proline (G and P)

favor disruption of the helix. This is particularly true for P since it is a pyrrolidine based imino acid (HN=) whose structure significantly restricts

movement about the peptide bond in which it is present, thereby, interfering with extension of the helix. The disruption of the helix is importantas it introduces additional folding of the polypeptide backbone to allow the formation of globular proteins.

-sheets
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Whereas an -helix is composed of a single linear array of helically disposed amino acids, -sheets are composed of 2 or more different regions

of stretches of at least 5-10 amino acids. The folding and alignment of stretches of the polypeptide backbone aside one another to form -sheetsis stabilized by H-bonding between amide nitrogens and carbonyl carbons.

Super-Secondary Structure

Some proteins contain an ordered organization of secondary structures that form distinct functional domains or structural motifs. Examples

include the helix-turn-helix domain of bacterial proteins that regulate transcription and the leucine zipper, helix-loop-helix and zinc finger

domains of eukaryotic transcriptional regulators. These domains are termed super-secondary structures.

Tertiary Structure of Proteins

Tertiary structure refers to the complete three-dimensional structure of the polypeptide units of a given protein. Included in this description is the

spatial relationship of different secondary structures to one another within a polypeptide chain and how these secondary structures themselvesfold into the three-dimensional form of the protein. Secondary structures of proteins often constitute distinct domains. Therefore, tertiary

structure also describes the relationship of different domains to one another within a protein. The interactions of different domains is governed by

several forces: These include hydrogen bonding, hydrophobic interactions, electrostatic interactions and van der Waals forces.

The elements of secondary structure are usually folded into a compact shape using a variety of loops and turns. The formation of tertiary

structure is usually driven by the burial of hydrophobic residues, but other interactions such as hydrogen bonding, ionic interactions and disulfide

bonds can also stabilize the tertiary structure. The tertiary structure encompasses all the noncovalent interactions that are not considered

secondary structure, and is what defines the overall fold of the protein, and is usually indispensable for the function of the protein.

Forces Controlling Protein Structure

Hydrogen Bonding

Polypeptides contain numerous proton donors and acceptors both in their backbone and in the R-groups of the amino acids. The environment in

which proteins are found also contains the ample H-bond donors and acceptors of the water molecule. H-bonding, therefore, occurs not only

within and between polypeptide chains but with the surrounding aqueous medium.


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Hydrophobic Forces

Proteins are composed of amino acids that contain either hydrophilic or hydrophobic R-groups. It is the nature of the interaction of the different

R-groups with the aqueous environment that plays the major role in shaping protein structure. The spontaneous folded state of globular proteins

is a reflection of a balance between the opposing energetics of H-bonding between hydrophilic R-groups and the aqueous environment and the

repulsion from the aqueous environment by the hydrophobic R-groups. The hydrophobicity of certain amino acid R-groups tends to drive themaway from the exterior of proteins and into the interior. This driving force restricts the available conformations into which a protein may fold.

Electrostatic Forces

Electrostatic forces are mainly of three types; charge-charge, charge-dipole and dipole-dipole. Typical charge-charge interactions that favor

protein folding are those between oppositely charged R-groups such as K or R and D or E. A substantial component of the energy involved in

protein folding is charge-dipole interactions. This refers to the interaction of ionized R-groups of amino acids with the dipole of the watermolecule. The slight dipole moment that exist in the polar R-groups of amino acid also influences their interaction with water. It is, therefore,

understandable that the majority of the amino acids found on the exterior surfaces of globular proteins contain charged or polar R-groups.

van der Waals Forces

There are both attractive and repulsive van der Waals forces that control protein folding. Attractive van der Waals forces involve the interactions

among induced dipoles that arise from fluctuations in the charge densities that occur between adjacent uncharged non-bonded atoms. Repulsive

van der Waals forces involve the interactions that occur when uncharged non-bonded atoms come very close together but do not induce dipoles.

The repulsion is the result of the electron-electron repulsion that occurs as two clouds of electrons begin to overlap. Although van der Waals

forces are extremely weak, relative to other forces governing conformation, it is the huge number of such interactions that occur in large proteinmolecules that make them significant to the folding of proteins.


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The 20 naturally occurring amino acids can be divided into several groups based on their chemical properties. Important factors are charge,

hydrophobicity/hydrophilicity, size and functional groups. The nature of the interaction of the different side chains with the aqueous environmentplays a major role in molding protein structure. Hydrophobic side chains tend to be buried in the middle of the protein, whereas hydrophilic side

chains are exposed to the solvent.

Examples of hydrophobic residues are: Leucine, isoleucine, phenylalanine, and valine, and to a lesser extent tyrosine, alanine and tryptophan.The charge of the side chains plays an important role in protein structures, since ion bonding can stabilize proteins structures, and an unpaired

charge in the middle of a protein can disrupt structures. Charged residues are strongly hydrophilic, and are usually found on the outside of

proteins. Positively charged side chains are found in lysine and arginine, and in some cases in histidine. Negative charges are found in glutamate

and aspartate. The rest of the amino acids have smaller generally hydrophilic side chains with various functional groups. Serine and threonine

have hydroxylgroups, and aspargine and glutamine have amide groups. Some amino acids have special properties such as cysteine, that can form

covalentdisulfide bondsto other cysteines, proline that is cyclical, and glycine that is small, and more flexible than the other amino acids.

Side chain conformation

The atoms along the side chain are named with Greek letters in Greek alphabetical order: , , , , and so on. C refers to the carbon atomclosest to the carbonyl group of that amino acid, C the second closest and so on. Side chains can be in different conformations called gauche(-),

trans and gauche(+).

Domains, motifs, and folds in protein structure

Many proteins are organized into several units. A structural domain is an element of the protein's overall structure that is self-stabilizing and

oftenfolds independently of the rest of the protein chain. Many domains are not unique to the protein products of one gene or one gene family

but instead appear in a variety of proteins. Protein structural motifs often include loops of variable length and unspecified structure, which in

effect create the "slack" necessary to bring together in space two elements that are not encoded by immediately adjacent DNA sequences in a

gene. Note also that even when two genes encode secondary structural elements of a motif in the same order, nevertheless they may specify

somewhat different sequences ofamino acids. This is true not only because of the complicated relationship between tertiary and primary

structure, but because the size of the elements varies from one protein and the next. Despite the fact that there are about 100,000 different

proteins expressed in eukaryotic systems, there are much fewer different domains, structural motifs and folds. This is partly a consequence ofevolution, since genes or parts of genes can be doubled or moved around within the genome. This means that, for example, a protein domain
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might be moved from one protein to another thus giving the protein a new function. Because of these mechanisms pathways and mechanisms

tends to be reused in several different proteins.

Protein folding

The process by which the higher structures form is called protein folding and is a consequence of the primary structure. A unique polypeptide

may have more than one stable folded conformation, which could have a different biological activity, but usually, only one conformation is

considered to be the active, or native conformation.

References

1. ^ PAULING L, COREY RB, BRANSON HR. Proc Natl Acad Sci U S A. 1951 Apr;37(4):205-11. The structure of proteins; two hydrogen-bondedhelical configurations of the polypeptide chain.PMID 14816373

2. ^ Quantum Pharmaceuticals software

Further reading

Habeck M, Nilges M, Rieping W (2005). "Bayesian inference applied to macromolecular structure determination".Physical review. E,Statistical, nonlinear, and soft matter physics72 (3 Pt 1): 031912. PMID 16241487. (Bayesian computational methods for the structure

determination from NMR data)
http://en.wikipedia.org/wiki/Protein_structure#cite_ref-pauling51_0-0%23cite_ref-pauling51_0-0http://www.ncbi.nlm.nih.gov/pubmed/14816373http://www.ncbi.nlm.nih.gov/pubmed/14816373http://en.wikipedia.org/wiki/Protein_structure#cite_ref-1%23cite_ref-1http://www.q-pharm.com/http://www.q-pharm.com/http://www.spineurope.org/publications/Habeck%20et%20al%20031912%202005.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/16241487http://en.wikipedia.org/wiki/Protein_structure#cite_ref-pauling51_0-0%23cite_ref-pauling51_0-0http://www.ncbi.nlm.nih.gov/pubmed/14816373http://en.wikipedia.org/wiki/Protein_structure#cite_ref-1%23cite_ref-1http://www.q-pharm.com/http://www.spineurope.org/publications/Habeck%20et%20al%20031912%202005.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/16241487


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Primary, Secondary, Tertiary and Quaternary Protein Structure

Adapted fromProtein Structure in Wikipedia
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Figure 1: Peptide bond linking two amino acids

Figure 2:Torsion (ordihedral) angles of the backbone

A protein is a naturally occuring polypeptide with a definite 3-dimensional structure.


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Figure 3: An alpha helix:

The backbone is formed as a helix.

An ideal alpha helix consists

of 3.6 residues per complete turn.

The side chains stick out.


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There are hydrogen bonds

between the carboxy group of amino acid nand the amino group of another amino acid .

Figure 4: An antiparallel beta sheet.Beta sheets are created,

when atoms of beta strands are hydrogen bound.

Beta sheets may consist of parallel strands,

antiparallel strands or out of a mixture

of parallel and antiparallel strands


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Figure 5: Chain B of Protein Kinase C Interacting Protein.

Helices are visualized as ribbons and

extended strands of betasheets by broad arrows.


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Figure 6: Quaternary structure of

Protein Kinase C Interacting Protein.

Protein Structure Notes_Level 1_Medical Students

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