Review the system of proteins folding
Module: Enzyme Technology and Biocatalysts
Module leader: Prof. Steve Forsythe
Proteins will be the bio molecules which play pivotal role in this living world. They are simply responsible for appearance of certain people in several types of cells and constitute around 50% of the full total cell dried mass. Proteins are the chain of amino acids which binds with polypeptide backbone and then flip in a distinctive 3D (indigenous) structure where protein expression occurs. Various pushes and factors are accountable for protein folding. If right manifestation of the protein will not come about, it'll cause disorders in body. Many diseases like Alzheimer's; Parkinson, cystic fibrosis etc (Baldwin 2007) is triggered due to inappropriate folding of proteins. For proper appearance of health proteins, the amino acid string should maintain its unique 3D composition. Sometimes proteins require assistance in folding, molecules which help in the folding are known as chaperones. These molecules assist in the folding of the certain proteins molecules and also avoid the unfolding of the molecules.
In this task, I have tried to describe the mechanism of the proteins folding and effect of various factors which affect protein folding by taking into consideration the present developments inside our understanding of thermodynamics and kinetics of health proteins.
Protein folding refers to the process by which a necessary protein assumes its quality framework, known as the indigenous state. Protein folding is highly complex mechanism and great development in its understanding has been achieved in last 20years because of the development and use of some complex modern techniques like X Ray Crystallography, N. M. R, and Mass Spectrometry etc. In the last few decades, we've managed to find the 3D framework of various proteins and how actually protein folding takes place. In the complicated process of proteins folding, various factors act together to construct specific 3D framework of a protein. Health proteins folding is a very quick process taking milliseconds to seconds.
Due to broadband of folding, it is not possible to find each and every possible conformation in fractions of your energy. Levinthal stated that every protein may possibly have millions of pathway where a desired 3D structure may be accomplished. By analysis of intermediates we can understand the device or pattern on which protein folding works. Nonetheless it is impossible to determine all possible structure of protein molecules.
Protein folding analysis uses denaturants which help to denature the necessary protein. The logic is to use denaturing conditions viz. high pH, Temperature, Pressure etc to avoid folding at intermediate periods (Stop flow approach) to review these intermediates, in that way generating an overview of the whole process. Fully folded structure is also called native structure. Protein folding studies are also done in in-vivo and in-vitro conditions. In in- vivo health proteins folding, some steel ions become cofactors. These cofactors stabilise and accelerate proteins folding and finally help achieve native level. Macromolecules like chaperones initiate protein folding, aiding the proteins molecule to retain its folded confirmation and so that it is stable. In-vitro concentration of macromolecules is very less, around 1% of what is originally within the cell. So inside cell, these molecules also influence protein stability and make them more secure than in vitro (Rumfeldt et al. 2008)
Protein folding can be considered a two levels or multistage process, depending after the type of sequence. An individual point mutation can change folding from two periods to multistage and vice-versa. Some past studies also show that protein sequences of significantly less than 80 proteins prefer two level folding and large protein sequences having more than 130 proteins prefer multi level folding. Later studies have shown that sequences rich in F and G amino acids prefer two levels folding where as sequences rich in C, H, L and R proteins prefer multistage folding (Ma, Chen & Zhang 2007)
Hydrophobic and hydrophilic interaction
Proteins are made of proteins and joined up with by polypeptide bonds causes development of polypeptide backbone. We have only 20 kind of the amino acids. whose combinations code for such intricate composition and folding. These amino acids can be separate in two communities some may be hydrophilic or polar group and other is hydrophobic or nonpolar group and their interaction with the cytoplasm make them folded(Trevino, Scholtz & Tempo 2007)
POLAR OR HYDROPHILIC AMINO ACID
NON-POLAR OR HYDROPHOBIC AMINO ACID
ASPARTIC ACID "D"
GLUTAMIC ACID "E"
In the first phases of research, problem was why protein folds to a specific composition and which part of the protein carried information for the folding and down the road this was realize that primary framework of the necessary protein code for the final 3D framework. Hydrophilic and hydrophobic connections of the proteins adjust necessary protein it such a means that it suffers minimum repulsion and problem from the encompassing. In folded state of necessary protein all hydrophilic amino acid molecules come at the other side and interact with drinking water in the cytoplasm and hydrophobic molecule come at the interior part of the molecule and don't show any effect and fascination with normal water molecules and ultimately protein folding happen in such a way that suffer minimum repulsion (Baldwin 2007)
All amino acids have different energetic in secondary structure. There are many chameleon sequences in necessary protein structure which is often considered as alpha helix or beta bed linens depending after the tertiary composition of necessary protein. These chameleon are stabilised by hydrophobic causes (Chen et al. 2008)
Fig. a shows yellowish coloring hydrophobic molecules inner aspect of structure
Fig. b shows folding takes place and maintains hydrophobic molecules in interior side
(Chen et al. 2008)
Apart from these connections hydrogen bonding is very important in the necessary protein folding.
"Hydrogen bonding takes place between hydrogen and electronegative atoms"
In the maintenance of the local composition hydrogen bonding within between the polypeptide amino acid chain which helpful in the formation of the supplementary, tertiary and quaternary structure of the protein. Hydrogen bonding also interacts between polar and side string residues with the encompassing water molecules. During the denaturing of the necessary protein hydrogen relationship between health proteins molecules rest and native structure of proteins disturbed (Djikaev, Ruckenstein 2010) Hydrophobic relationships are also accountable for the proteins folding. During hydrophobic interactions amino acids that are non polar or hydrophobic they align themselves in such a way that all hydrophobic get together and all hydrophilic molecules make hydrogen bonds with normal water molecules, all hydrophobic amino acid come directly into inner side of the proteins molecules and development of the nuclei take place which is hydrophobic these relationship further helpful in the secondary, tertiary structure and for this reason health proteins stabilise and help to achieve native composition because hydrophobic molecules won't interact with water and will have repulsive frame of mind toward water and allow proteins in the folded form and finally such type of the folding happen in which molecule have hydrophobic main and all hydrophilic molecules in periphery of the folded structure(Berezovsky et al. 2001)
Free energy and entropy (G, E)
Gibbs free energy (G) is also thought as the amount of the energy which is free and this can also be thought as the way of measuring unstableness which assessed by simple equation
G=free energy, H=enthalpy, S=entropy, T= temperature
Entropy (S) is defined as amount of randomness in virtually any system, in conditions of health proteins folding this can be define as the measure of the possible composition in the protein molecule at that value of the entropy. Entropy is accountable for the possible out come of necessary protein as much high would be entropy as much lot of the confirmation would form. To minimise the entropy in the necessary protein folding various force come in play like hydrogen bonds, salt bridges, disulphide bonds etc. these bonds help to reduce the entropy and favour protein folding(Brady, Clear 1997)BOLTZMANN done the entropy and give us a very useful relationship between atomic theory and entropy. Boltzmann suggested an equation which shows that entropy in any unfolded protein structure is add up to the merchandise of his constant(KB) and natural log of amount of most possible expresses which any necessary protein can adopt(S)
S = KB * NATURAL LOG (S)
Protein folding prefers low value of entropy and uses that smallest journey in which value of entropy is low. At different value of the entropy different amount of structure could be present and lastly all framework will vanished and one composition would be there at the minimum value of entropy, which is our local framework (Weikl, Dill 2003)
Enthalpy (H) is also accountable for protein folding. This is also called the way of measuring the full total energy of the system including internal energy (U). P and V are the pressure and volume of system
So, we should seek out such structure that have low value of enthalpy then your free energy, because which structure have low value of enthalpy that will have low value of free energy too(Brockwell, Smith & Radford 2000)
Gibbs free energy formula is the sole solution for those protein folding problem. Gibbs formula shows that in case of protein folding, secure point out will have minimum value of "G". unfolded state have higher free energy then your folded one and proteins folding have many intermediates, This level is less filled stage and also have maximum energy in the whole system, all above talk about factor in the Gibbs formula adjust and finally provide such folded state where value of "G" is minimum amount and this is recognized as fully folded and steady verification(Finkelstein, Badretdinov 1997)
(www. biology-online. org/articles/statistical_thermodynamics_taking_walk. html)
Chaperones are bio substances which participate in the protein folding. Protein need assistance in the folding and binds with cofactors. which allow them to fold properly. these cofactor known as chaperones. These chaperones bind with the necessary protein as N terminus of the health proteins shaped and leave ribosome and until and unless protein gain his fully active 3D express and be functional(Tomala, Korona 2008) Chaperones aren't only assisting in the right protein folding but they also help protein to keep up its accurate 3D structure and prevent these to unfold. these substances comes in to experience when cell is "under stress" credited to favourable conditions aren't present plus they also called the H. S. P (high temperature shock proteins). these molecular chaperones are HSP40(Dnaj), HSP60(GroEl), HSP70(Dnak) etc. (Rikhvanov, Romanova & Chernoff 2007)
Copied from Yon, Betton 1991
Mode of action
"Chaperones recognise non native protein framework by their open hydrophobic regions"
Chaperones action is motivated by ATP and then for the activity of the chaperones assistance health proteins folding need of energy, which is provided by the ATP. These chaperones bind with the intermediate and unfolded health proteins framework by the utilisation of the ATP intermediates or random coil framework are unfolded and again these are fold in the correct 3D composition (NATIVE structure).
They prevent aggregation and misfolding of recently synthesised protein substances.
They unfold intermediate and then collapse them properly in to native structure
Chaperones are like catalyst, they enhance rate of necessary protein folding and assist proteins folding to native structure and after the creation of the local structure they segregated. As like catalyst they required energy for the initiation of the process
Chaperones activity is much specialised, in stress condition health proteins get mutated, denature, and aggregate. Which may cause some wrong expression and code for some disease. In such situations they are simply enough capable to provide personalised treatment to different necessary protein (Yon, Betton 1991)They may easily point out that which protein intermediate composition need to be degraded and which protein intermediate to be stabilise in the local structure and avenue should be follow for this process. In a few mutation destabilise proteins can be easily stabilized by HSP70 and some over manifestation of the precise chaperones. For example: In bacteria HSP70 bind with the health proteins polypeptide string during translation after the synthesis some health proteins released for manifestation plus some may attached for some specialised folding & most destabilise polypeptide chain degraded by chaperones (Tomala, Korona 2008)
Chaperones activity is not simple they have got multiple steps in their folding system. Some chaperones required various other chaperones intermediate as substrate and they provide native composition.
Hsp90/70 mechanism chain
Some chaperones may in charge of disease. it has been discovered that HSP90 enhance tumor development because many mutated health proteins mature in the presence of the HSP90 and cause tumor, repressing HSP90 such type of cancer can be able to prevent but problem associated with this is because of this step some non mutagenic protein will be degrade rather than exhibit and cause problem. But on other side HSP70 acts nearly as good repressor in neurodegenerative disease and stop this disease in the fruits flies (Tomala, Korona 2008)
Models of necessary protein modelling and composition prediction
Plaxco and co-worker model:
This model demonstrates high degree of correlation between folding rate and structural properties of necessary protein explain on the basis of contact order (CO). This can be cross validated from various tests that folding rate and contact order are reliant to each other.
L is the sequence length
N is the full total quantity of inter-residue atomic contacts
‹Lij is the collection separation of getting in touch with residues i and j
Kuznetsov and rackovsky exhibited that structural structured determinants can serve nearly as good determinants of folding rate and many other researchers searching for which structural and collection centered determinants can provide as unique predictor of foldable rate (Shakhnovich 2006)
Dokholyan and co-workers model:
They use simple proteins model and discover transition talk about of src homology 3(SH3) to discover contribution of each amino acid in move state. They calculate ‹ value and on this basis they find high relationship between simulation and experimental ‹ value. in the long run of these experimental model they conclude that L24 and G24 are two most significant residues in the folding of proteins
Physics and bioinformatics structured models:
Conformational changes in protein
Mechanism of foldable, enzyme catalysis, method of action protein
Response to ph sodium and denaturants(Brockwell, Smith & Radford 2000)
Bioinformatics is very important tool to determine the structure and folding pattern of the necessary protein molecules. With this we add our computer established program along with these physics model and within the portion of the time provide us 3D framework of proteins. Various directories on web can be found which contain information regarding proteins only like NCBI, PUBMED etc. these directories contain all information about proteins by the comparability of our unknown collection using bioinformatics tools with these databases we will get out possible composition and folding structure and helpful in medicine discovery, possible treatment against disease etc.
Now, how collectively these factors works
After having the knowledge of these factors now we can simply understand how they take action and lead to the totally folded 3D structure. Primary composition of necessary protein code for 3D structure and all above factors get involved to provide a functional unit. primarily primary framework of protein are constructed of different kind of proteins on the poly peptide back again bone and soon after the creation of the N-terminus health proteins folding begins and secondary constructions alpha helix and beta bedding are made.
In alpha helix all amino acid chain stay in the periphery of the helix and this structure formed anticipated to hydrogen bonding and di-sulphide bonding (Trevino, Scholtz & Speed 2007)
After the forming of secondary structure, tertiary framework these hydrophobic connections, hydrogen bonding and charge on the molecule come it to the play now this proteins molecule structure fold in such a way to minimise each one of these forces and make an effort to give an secure verification to protein(Chen et al. 2008)
Free energy and entropy function simultaneously. After connection of these extra structures steadiness is not homogeneous in the complete tertiary structure. There could be probability that two stable structures are becoming a member of by unpredictable and less steady strands and in that case folding happen so to minimise the free energy of the machine. This sort of stage is recognized as the intermediate level. In this stage all amino acids are fastened in the structure however the entropy of the machine is high and scheduled to which this show high occurrence of free energy and may have the millions of the possibilities of the intermediate framework. Now protein starts off folding from intermediate to the steady or native structure by minimising the conversation between the substances. Because of which all the hydrophobic or non polar amino acid come at the heart of the framework and the forming of hydrophobic core take place of 3D composition and everything polar or hydrophilic molecules come at the periphery of the 3D structure(Chen et al. 2008). Out of millions of the options there are many avenue which favour this folding in term of having least energy and necessary protein molecule select that course which is shortest which may contain several steps in folding and ultimately triggers the formation of indigenous 3D structure
Copied from Ma, Chen & Zhang 2007
There is actually some equilibrium in some folded and intermediates express and molecules may be aggregate. this depend after the pH, Temperature, Pressure and denaturation agents and the health proteins framework destabilise it start influencing other native proteins structure in this stage chaperones act as cofactors and assist in the and retaining native composition of protein(Ma, Chen & Zhang 2007)
In the proteins folding 3D structure of protein plays an important role in the health proteins manifestation and their function. Information regarding health proteins folding exists in the principal structure of the protein which bioenergetics can be determined by bound amino acid. Hydrophobic pushes play an important role. Each of them concentrate at the centre of the substances and hydrophilic at the periphery of the structure. Hydrogen bonding takes on an important role scheduled to which all polar molecules bound with the surrounding medium in cell and makes proteins molecule structure rigid and compressed.
Protein folding is a spontaneous process in which entropy of the molecule is lessening and finally offers a folded structure. Health proteins native structure must have low value of Gibbs free energy, entropy, and enthalpy and lower the value, higher would be the degree of protein stability. Proteins may unfold due to the presence of the unfavourable condition like temperature, pressure, pH, and denaturing agent. When this happens special kind of molecules assist in the folding known as chaperones and helpful in retaining native composition of protein.
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