ИСТИНА

It has been realized that conformational flexibility of a protein structure can be crucial for its function; however, modeling of this phenomenon is limited by a high computational cost. Hybrid HPC-architectures enable routine calculations at a previously intractable scale and we have used it to accelerate simulations of protein dynamics at studying function and regulation: to reveal a structural organization of Neuraminidase A from Streptococcus pneumoniae whose catalytic and lectin domains are separated by a flexible linker, and to study how this unique structure is involved in the pneumococcal biofilm formation; to discover a novel allosteric site in Glyceraldehyde 3-phosphate dehydrogenase from Mycobacterium tuberculosis whose ability to interact with regulatory ligands depends on the particular conformation of its dynamic structure, and to select complementary inhibitors. In a separate development, a bioinformatic and statistical model describing a protein backbone flexibility based on a 3D-motif analysis was used to improve both stability and activity of a PLP-dependent threonine aldolase from Aeromonas jandaei by introducing a single S-S bond that does not meet the geometry criteria for a disulfide bond formation in the static crystallographic structure. Recent advances in computational technologies reveal new opportunities to simulate structural behavior of proteins on the timescales relevant for biology, while assessing protein flexibility by 3D-motifs – patterns of local structure associated with function – can provide an attractive alternative to molecular modeling. The work related to molecular modeling was funded by Russian Science Foundation [15-14-00069-P] and the work related to the 3D-motif analysis by the Russian Foundation for Basic Research [18-29-13060]. Supercomputer modeling was performed using the HPC computing resources at the Lomonosov Moscow State University supported by the project RFMEFI62117X0011.