Folding problem

Both the structural and kinetic aspects of the protein-folding problem are complicated by the fact that folding takes place within a bath of water molecules. In fact, hydrophobic interactions are almost certainly crucial for both the relation of the sequence and the native structure, and the process by which a good sequence folds to its native structure. 

Most reactions in cells are carried out by enzymes [1], In many instances the rates of enzyme-catalysed reactions are enhanced by a factor of a million. A significantly large fraction of all known enzymes are proteins which are made from twenty naturally occurring amino acids. The amino acids are linked by peptide bonds to fonn polypeptide chains. The primary sequence of a protein specifies the linear order in which the amino acids are linked. To carry out the catalytic activity the linear sequence has to fold to a well defined tliree-dimensional (3D) stmcture. In cells only a relatively small fraction of proteins require assistance from chaperones (helper proteins) [2]. Even in the complicated cellular environment most proteins fold spontaneously upon synthesis. The detennination of the 3D folded stmcture from the one-dimensional primary sequence is the most popular protein folding problem. 

How to design sequences tliat adopt a specified fold [9] This is tire inverse protein folding problem tliat is vital to the biotechnology industry. There are some proteins tliat do not spontaneously reach tire native confomiation. In tire cells tliese proteins fold witli tire assistance of helper molecules referred to as chaperonins. The chaperonin-mediated folding problem involves an understanding of tire interactions between proteins. 

Biological infonnation is also concerned witli tire analysis of biological messages and tlieir import. The fundamental premise of tire protein-folding problem section C2.14.2.2 is tliat tire full tliree-dimensional arrangement of tire protein molecule can be predicted, given only tire amino acid sequence, together witli tire solvent composition, temperature and pressure. One test of tire validity of tliis premise is to compare tire infonnation content of tire sequence witli tire infonnation contained in tire stmcture [169]. The fonner can be obtained from Shannon s fonnula ... 

Fernandez A and Colubri A 1998 Microscopic dynamics from a coarsely defined solution to the protein folding problem J. Math. Phys. 39 3167-87... 

The protein folding problem is the task of understanding and predicting how the information coded in the amino acid sequence of proteins at the time of their formation translates into the 3-dimensional structure of the biologically active protein. A thorough recent survey of the problems involved from a mathematical point of view is given by Neumaier [22]. 

C.D. Maranas, IP. Androulakis and C.A. Floudas, A deterministic global optimization approach for the protein folding problem, pp. 133-150 in Global minimization of nonconvex energy functions molecular conformation and protein folding (P. M. Pardalos et al., eds.), Amer. Math. Soc., Providence, RI, 1996. 

The most ambitious approaches to the protein folding problem attempt to solve it from firs principles (ab initio). As such, the problem is to explore the coirformational space of th molecule in order to identify the most appropriate structure. The total number of possibl conformations is invariably very large and so it is usual to try to find only the very lowes energy structure(s). Some form of empirical force field is usually used, often augmente with a solvation term (see Section 11.12). The global minimum in the energy function i assumed to correspond to the naturally occurring structure of the molecule. 

Chan H S and K A Dill 1993. The Protein Folding Problem. Physics Today Feb 24-32. 

The techniques listed above are dynamical simulations. It is also possible to use bead interaction potentials for strictly thermodynamic calculations. For example, the following steps have been used for protein-folding problems ... 

Finding the minimum of the hybrid energy function is very complex. Similar to the protein folding problem, the number of degrees of freedom is far too large to allow a complete systematic search in all variables. Systematic search methods need to reduce the problem to a few degrees of freedom (see, e.g.. Ref. 30). Conformations of the molecule that satisfy the experimental bounds are therefore usually calculated with metric matrix distance geometry methods followed by optimization or by optimization methods alone. 

A Godzik, A Kolinski, J Skolmck. Topology fingerprint approach to the inverse protein folding problem. J Mol Biol 227 227-238, 1992. 

M Sippl. Who solved the protein folding problem Structure 7 R81-R83, 1999. 

To understand the biological function of proteins we would therefore like to be able to deduce or predict the three-dimensional structure from the amino acid sequence. This we cannot do. In spite of considerable efforts over the past 25 years, this folding problem is still unsolved and remains one of the most basic intellectual challenges in molecular biology. 

With the realization that there are only a limited number of stable folds and many unrelated sequences that have the same fold, biologically oriented computer scientists started to address what is called the inverse folding problem namely, which sequence patterns are compatible with a specific fold If this question can be answered, such patterns could be used to search through the genome sequence databases and extract those sequences that have a specific fold, such as the cx/p barrel or the immunoglobulin fold. 

The ultimate goal of protein engineering is to design an amino acid sequence that will fold into a protein with a predetermined structure and function. Paradoxically, this goal may be easier to achieve than its inverse, the solution of the folding problem. It seems to be simpler to start with a three-dimensional structure and find one of the numerous amino acid sequences that will fold into that structure than to start from an amino acid sequence and predict its three-dimensional structure. We will illustrate this by the design of a stable zinc finger domain that does not require stabilization by zinc. 

This branch of bioinformatics is concerned with computational approaches to predict and analyse the spatial structure of proteins and nucleic acids. Whereas in many cases the primary sequence uniquely specifies the 3D structure, the specific rules are not well understood, and the protein folding problem remains largely unsolved. Some aspects of protein structure can already be predicted from amino acid content. Secondary structure can be deduced from the primary sequence with statistics or neural networks. When using a multiple sequence alignment, secondary structure can be predicted with an accuracy above 70%. 

Herschlag D (1995) RNA chaperones and the RNA folding problem. J Biol Chem 270 20871-20874... 

Proteins fold on a time scale from [is to s. Starting from a random coil conformation, proteins can find their stable fold quickly although the number of possible conformations is astronomically high. The protein folding problem is to predict the folding and the final structure of a protein solely from its sequence. 

Protein Folding Problem Protein Kinase Protein Kinase A Protein Kinase C Protein Kinase Inhibitors Protein Phosphatases Protein Sorting... 

Presently, a single theory of protein folding that simultaneously solves the three problems does not exist. Separate approaches to each problem have progressed toward separate solutions. Of these, the folding problem is understood best, but the most fruitful approach there can be used neither to predict nor to design real protein structures. 

Dinner, A. R., and Karplus, M. (2001). Comment on the communication The key to solving the protein-folding problem lies in an accurate description of the denatured state by van Gunsteren et al. Angew. Chem. Int. Ed. 40, 4615-4616. 

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