![]() This is a major reason why development and practical applications of coarse-grained protein modeling methods is needed. Similar limitations apply to molecular docking, studies of dynamics of biomacromolecular systems, and other related tasks. (14) Even using a special-purpose supercomputer dedicated to atomistic molecular dynamics (MD) simulations, (15) it is possible to simulate folding processes of only small, relatively fast folding proteins (16, 17) or their dimerization processes (18) (see Figure 1). (7-13) Classical atom-level molecular modeling can address many of the these tasks, but its practical applications are still limited by its algorithmic efficiency and the available computing power. Computational modeling of these processes is crucial for creating realistic molecular pictures of biological protein functions, interpretation of different experimental data, knowledge-based drug design and various aspects of biotechnology, etc. Native structures are not completely fixed, (4-6) but they change when proteins perform their biological function, interact with other biomacromolecules, or undergo unfolding–folding transitions. (3) Theoretical prediction of folded (native-like) three-dimensional protein structures is just one of the key tasks of computational structural biology. This is still only a small fraction of proteins with known sequences, (2) although for a large fraction of sequenced proteins their three-dimensional structures can be predicted theoretically by various combinations of bioinformatics and molecular modeling techniques. Owing to the impressive progress in the experimental methods of molecular biology in the last decades we now know around 120 thousand three-dimensional native-like protein structures or their complexes, with resolutions from about 0.5 to 2–3 Å. Protein folding plays an essential functional role in living cells, although this process could be also observed at properly controlled in vitro experiments. (1) The majority of known natural proteins fold into specific three-dimensional structures, while the vast majority of random polypeptides collapse to somewhat less dense unstructured states. While sequences of amino acid units in natural proteins look at first glance random, they are certainly not. ![]() Since typical protein chains consist of a few tens to hundreds of amino acids, the number of possible amino acid sequences of such copolymers is enormous. Again with some exceptions, all amino acids in living organisms have left-handed conformations. With some exceptions, proteins are composed of 20 types of amino acids. ![]() Living organisms are the most complex chemical systems whose function depends on a vast number of molecules, from simple monomers through many small and medium-size oligomers and copolymers (peptides, proteins, RNA, etc.) to huge copolymers such as DNA.
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