Browsing by Author "Kochugaeva, Maria P."

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    Elucidating the correlations between cancer initiation times and lifetime cancer risks
    (Springer Nature, 2019) Teimouri, Hamid; Kochugaeva, Maria P.; Kolomeisky, Anatoly B.
    Cancer is a genetic disease that results from accumulation of unfavorable mutations. As soon as genetic and epigenetic modifications associated with these mutations become strong enough, the uncontrolled tumor cell growth is initiated, eventually spreading through healthy tissues. Clarifying the dynamics of cancer initiation is thus critically important for understanding the molecular mechanisms of tumorigenesis. Here we present a new theoretical method to evaluate the dynamic processes associated with the cancer initiation. It is based on a discrete-state stochastic description of the formation of tumors as a fixation of cancerous mutations in tissues. Using a first-passage analysis the probabilities for the cancer to appear and the times before it happens, which are viewed as fixation probabilities and fixation times, respectively, are explicitly calculated. It is predicted that the slowest cancer initiation dynamics is observed for neutral mutations, while it is fast for both advantageous and, surprisingly, disadvantageous mutations. The method is applied for estimating the cancer initiation times from experimentally available lifetime cancer risks for different types of cancer. It is found that the higher probability of the cancer to occur does not necessary lead to the faster times of starting the cancer. Our theoretical analysis helps to clarify microscopic aspects of cancer initiation processes.
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    Mechanisms of Protein Search for Targets on DNA: Theoretical Insights
    (MDPI, 2018) Shvets, Alexey A.; Kochugaeva, Maria P.; Kolomeisky, Anatoly B.
    Protein-DNA interactions are critical for the successful functioning of all natural systems. The key role in these interactions is played by processes of protein search for specific sites on DNA. Although it has been studied for many years, only recently microscopic aspects of these processes became more clear. In this work, we present a review on current theoretical understanding of the molecular mechanisms of the protein target search. A comprehensive discrete-state stochastic method to explain the dynamics of the protein search phenomena is introduced and explained. Our theoretical approach utilizes a first-passage analysis and it takes into account the most relevant physical-chemical processes. It is able to describe many fascinating features of the protein search, including unusually high effective association rates, high selectivity and specificity, and the robustness in the presence of crowders and sequence heterogeneity.
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    Optimal Length of Conformational Transition Region in Protein Search for Targets on DNA
    (American Chemical Society, 2017) Kochugaeva, Maria P.; Berezhkovskii, Alexander M.; Kolomeisky, Anatoly B.
    The starting point of many fundamental biological processes is associated with protein molecules finding and recognizing specific sites on DNA. However, despite a large number of experimental and theoretical studies on protein search for targets on DNA, many molecular aspects of underlying mechanisms are still not well understood. Experiments show that proteins bound to DNA can switch between slow recognition and fast search conformations. However, from a theoretical point of view, such conformational transitions should slow down the protein search for specific sites on DNA, in contrast to available experimental observations. In addition, experiments indicate that the nucleotide composition near the target site is more symmetrically homogeneous, leading to stronger effective interactions between proteins and DNA at these locations. However, as has been shown theoretically, this should also make the search less efficient, which is not observed. We propose a possible resolution of these problems by suggesting that conformational transitions occur only within a segment around the target where stronger interactions between proteins and DNA are observed. Two theoretical methods, based on continuum and discrete-state stochastic calculations, are developed, allowing us to obtain a comprehensive dynamic description for the protein search process in this system. The existence of an optimal length of the conformational transition zone with the shortest mean search time is predicted.