Сборник содержит материалы научной мультиконференции «Биотех- нология медицине будущего»

ПОСТЕРНАЯ СЕССИЯ

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Всероссийская мультиконференция с международным участием «Биотехнология – медицине будущего»
29 июня - 2 июля 2019 г., г. Новосибирск, Россия
136
Molecular dynamics pipeline for predicting the effects of cancer-associated 
amino acid substitutions: Identification of new OGG1 somatic variants
with low activity
Popov A.V.
1,2
, Endutkin A.V.
1,2
, Barmatov A.E.
1
, Makasheva K.A.
2
, Yatsenko D.D.
2
, 
Raspopova D.Yu.
2
, Zharkov D.O.
1,2
1
SB RAS Institute of Chemical Biology and Fundamental Medicine, Novosibirsk, Russia 
2
Novosibirsk State University, Novosibirsk, Russia
Progress in modern sequencing methods has allowed increasingly personalized antitumor 
therapy. To enhance the power of personalization, data on the functionality of tumor-
associated variants of proteins involved in the response to DNA damage are of considerable 
interest. Particular attention today is paid to predictions of the functionality of protein variants 
by computational methods. However, the vast majority of such methods are presently based 
on the phylogenetic information and barely use the modern possibilities of computational 
analysis of the structure and dynamics of proteins.
We have employed molecular dynamics simulation to model the structures of mutant 
variants, observed in clinical tumor samples, of human 8-oxoguanine-DNA glycosylase 
(OGG1), a protein belonging to the base excision repair system. This enzyme reduces the 
cytotoxicity of several classes of anticancer drugs, including thiotepa, bleomycin, cisplatin, etc. 
The enzymatic activity of these mutant variants has been determined in parallel.
We have developed a software pipeline to automate the retrieval and preparation of many 
similar structures differing only by amino acid substitutions, for feeding into molecular 
dynamics simulation programs. Trajectories of a random sample of mutant variants of OGG1 
were obtained. The predicted functionality of all known mutant OGG1 variants found in 
human cancers was classified according to the results of four algorithms using only phyloge-
netic information (SIFT, FATHMM, MutationTaster and PROVEAN), and compared with the 
classification of OGG1 mutants based on the results of molecular dynamics. We have purified 
a series of mutant OGG1 proteins and characterized them biochemically, establishing that 
OGG1 I145M and R161W variants found in esophageal squamous cell carcinoma and colon 
adenocarcinoma, respectively, have a significantly reduced enzymatic activity. Within the set 
of 11 experimentally characterized mutant variants, molecular dynamics analysis showed
a better correlation with experimental results than did predictions by phylogenetic methods.
This study was supported by RSF (grant 18-74-00052).

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Всероссийская мультиконференция с международным участием «Биотехнология – медицине будущего»
29 июня - 2 июля 2019 г., г. Новосибирск, Россия
137