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1

Theoretical approach to the common events in every living cell – protein folding and protein misfolding

Vaibhav V. K., Sachin S. L.

International Letters of Chemistry, Physics and Astronomy

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2012

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Vol. 3

41-51

EN

Folding and unfolding are crucial ways of regulating biological activity and targeting proteins to different cellular locations. Aggregation of misfolded proteins that escape the cellular quality-control mechanisms is a common feature of a wide range of highly debilitating and increasingly prevalent diseases. Protein misfolding is a common event in living cells. Molecular chaperones not only assist protein folding; they also facilitate the degradation of misfolded polypeptides. Protein folding is governed solely by the protein itself, scientists discovered that some proteins have helped in the process called chaperones. When the intracellular degradative capacity is exceeded, juxtanuclear aggresomes are formed to sequester misfolded proteins. Misfolding of newly formed proteins not only results in a loss of physiological function of the protein but also may lead to the intra- or extra- cellular accumulation of that protein. A number of diseases have been shown to be characterised by the accumulation of misfolded proteins, notable example being Alzheimer's disease.

2

O kilku osobliwościach w oddziaływaniach molekuł

Piela L.

Wiadomości Chemiczne

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2011

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[Z] 65, 11-12

935-952

EN

The ground state electronic energy represents a complicated function of the nuclear coordinates. Even for relatively small molecules this function may have many minima in the corresponding "energy landscape", very often myriads of minima, each of them corresponding to a stable configuration of the nuclei. This is why predicting the lowest-energy conformation or configuration represents a formidable task. There were many attempts to solve this problem for protein molecules, for which it is believed their native conformation corresponds to the lowest free energy. The challenge to find this conformation from a given sequence of amino acids is known as a "second genetic code". In fact all of these attempts based on some smoothing of the energy landscape. In the article some of these smoothing techniques are described, from a generic one to those, which finally turned out to be highly successful in finding native structures of globular proteins. When discussing the contributions to the conformational energy the importance of the hydrophobic effect as well as of the electrostatic interactions has been stressed. In particular it turned out that the dipole moments of the NH and of the CO bonds in proteins functioning in nature are oriented to good accuracy along the local intramolecular electric field. Thanks to enormous effort of the protein folding community it is possible to design such amino acid sequences, which fold to the desired protein 3D structure. A certain reliable theoretical technique of protein folding has been used to study a possibility of conformational autocatalysis. It turned out that a small protein of 32 amino acids, with carefully predesigned amino acid sequence, exhibits indeed such an effect, which may be seen as a model of the prion disease propagation.

3

Elements of non-random structure in the unfolded states of proteins : location and possible implications for protein folding mechanisms

Nikiforovicz G. V.

Polimery

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2003

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T. 48, nr 1

44-49

EN

This study introduces a simple computational procedure to search protein sequences for the segments with above average propensity to adopt non-random structures (which includes the native-like structure) in the unfolded state. The procedure consists of systematical conformational analysis of all overlapping hexapeptide segments in the protein sequence. The main aim of the computational approach is to determine the 3D structure most preferable for a given residue in the protein sequence, as determined by local interactions within the set of hexapeptides featuring the particular residue under consideration. Specifically, this study focuses on four types of "template" 3D structures that may be adopted by a hexapeptide, namely beta-strand, alpha-helix, beta-turn and the native-like structure of the folded state (assumed to be known). The study discusses also the possible importance of such segments for the different molecular mechanism of folding of the two prototypical proteins, namely the 65-residue barley chymotrypsin inhibitor 2 (CI2) and the 110-residue ribonuclease from Bacillus anzyloliquefaciens (barnase). The computational results suggest that dynamic equilibrium in the unfolded state for the continuous fragment 6-27 in CI2 will likely prefer the native-like structure that may be preserved during folding. For barnase, oil the contrary, dynamic equilibrium preferring the native-like structure most likely will occur in the unfolded state only at several small separate fragments, so the large non-native non-random segments of the unfolded state have to be restructured during folding.

PL

Opracowano prostą procedurę obliczeniową do badania sekwencji białek w odniesieniu do segmentów o większej niż średnia skłonności do przybierania postaci struktur uporządkowanych (które zawierają struktury takie same jak macierzyste) w stanie rozwiniętym. Procedura obejmuje systematyczną analizę konformacyjną wszystkich nachodzących na siebie segmentów heksapeptydowych w sekwencji białka. Głównym celem tego przybliżenia obliczeniowego jest określenie najbardziej uprzywilejowanej w przypadku danych reszt aminokwasowych w sekwencji białkowej struktury 3D, zgodnej z wynikami uzyskanymi na podstawie oceny lokalnych oddziaływań w układzie heksapeptydów obrazujących rozważane tu reszty aminokwasów. Skupiono się zwłaszcza na (przyjętych jako znane) czterech typach matrycowych struktur 3D, które mogą być przybierane przez heksapeptydy, mianowicie na strukturze P (fi-strand), a-helisy (a-helix), P-zgiętej ($-turn) oraz na strukturze takiej jak macierzysta w stanie rozwiniętym. Przedyskutowano także możliwy udział takich segmentów w różnych molekularnych mechanizmach zwijania dwu prototypowych białek: złożonego z 65 reszt aminokwasowych inhibitora 2-chymotrypsyny jęczmienia (C12) oraz 110-aminokwasowej rybonukleazy z Bacillus amyloliąuefaciens (barnazy). Wyniki obliczeń wskazują, że równowaga dynamiczna w stanie rozwiniętym ciągłego fragmentu 6-27 w C12 powinna preferować struktury takie jak macierzyste, które mogą zostać zachowane podczas zwijania (rys. 1 i 3). Przeciwnie, w przypadku barnazy równowaga dynamiczna uprzywilejowująca struktury podobne macierzystym najczęściej występuje w stanie rozwiniętym tylko w nielicznych małych wydzielonych fragmentach, zatem duże niemacierzys-te uporządkowane segmenty w tym stanie muszą być odtworzone podczas zwijania.