R-3 Repository :: Browsing by Author "Kolomeisky, Anatoly B."

Browsing by Author "Kolomeisky, Anatoly B."

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A deterministic model for one-dimensional excluded flow with local interactions
(Public Library of Science, 2017) Zarai, Yoram; Margaliot, Michael; Kolomeisky, Anatoly B.
Natural phenomena frequently involve a very large number of interacting molecules moving in confined regions of space. Cellular transport by motor proteins is an example of such collective behavior. We derive a deterministic compartmental model for the unidirectional flow of particles along a one-dimensional lattice of sites with nearest-neighbor interactions between the particles. The flow between consecutive sites is governed by a “soft” simple exclusion principle and by attracting or repelling forces between neighboring particles. Using tools from contraction theory, we prove that the model admits a unique steady-state and that every trajectory converges to this steady-state. Analysis and simulations of the effect of the attracting and repelling forces on this steady-state highlight the crucial role that these forces may play in increasing the steady-state flow, and reveal that this increase stems from the alleviation of traffic jams along the lattice. Our theoretical analysis clarifies microscopic aspects of complex multi-particle dynamic processes.
A general theoretical framework to design base editors with reduced bystander effects
(Springer Nature, 2021) Wang, Qian; Yang, Jie; Zhong, Zhicheng; Vanegas, Jeffrey A.; Gao, Xue; Kolomeisky, Anatoly B.; Center for Theoretical Biological Physics
Base editors (BEs) hold great potential for medical applications of gene therapy. However, high precision base editing requires BEs that can discriminate between the target base and multiple bystander bases within a narrow active window (4 – 10 nucleotides). Here, to assist in the design of these optimized editors, we propose a discrete-state stochastic approach to build an analytical model that explicitly evaluates the probabilities of editing the target base and bystanders. Combined with all-atom molecular dynamic simulations, our model reproduces the experimental data of A3A-BE3 and its variants for targeting the “TC” motif and bystander editing. Analyzing this approach, we propose several general principles that can guide the design of BEs with a reduced bystander effect. These principles are then applied to design a series of point mutations at T218 position of A3G-BEs to further reduce its bystander editing. We verify experimentally that the new mutations provide different levels of stringency on reducing the bystander editing at different genomic loci, which is consistent with our theoretical model. Thus, our study provides a computational-aided platform to assist in the scientifically-based design of BEs with reduced bystander effects.
A New Theoretical Approach to Analyze Complex Processes in Cytoskeleton Proteins
(American Chemical Society, 2014) Li, Xin; Kolomeisky, Anatoly B.; Center for Theoretical Biological Physics
Cytoskeleton proteins are filament structures that support a large number of important biological processes. These dynamic biopolymers exist in non-equilibrium conditions stimulated by hydrolysis chemical reactions in their monomers. Current theoretical methods provide a comprehensive picture of biochemical and biophysical processes in cytoskeleton proteins. However, the description is only qualitative at biologically relevant conditions because utilized theoretical mean-field models neglect correlations. We develop a new theoretical method to describe dynamic processes in cytoskeleton proteins that takes into account spatial correlations in the chemical composition of these biopolymers. Our approach is based on analysis of probabilities of different clusters of subunits. It allows us to obtain exact analytical expressions for a variety of dynamic properties of cytoskeleton filaments. By comparing theoretical predictions with Monte Carlo computer simulations it is shown that our method provides a fully quantitative description of complex dynamic phenomena in cytoskeleton proteins at all conditions.
Accuracy of Substrate Selection by Enzymes Is Controlled by Kinetic Discrimination
(American Chemical Society, 2017) Banerjee, Kinshuk; Kolomeisky, Anatoly B.; Igoshin, Oleg A.; Center for Theoretical Biological Physics
Enzymes have the remarkable ability to select the correct substrate from the pool of chemically similar molecules. The accuracy of such a selection is determined by differences in the free-energy profiles for the right and wrong reaction pathways. Here, we investigate which features of the free-energy landscape govern the variation and minimization of selectivity error. It is generally believed that minimal error is affected by both kinetic (activation barrier heights) and thermodynamic (binding stability) factors. In contrast, using first-passage theoretical analysis, we show that the steady-state selectivity error is determined only by the differences in transition-state energies between the pathways and is independent of the energies of the stable complexes. The results are illustrated for two common catalytic mechanisms: (i) the Michaelis–Menten scheme and (ii) an error-correcting kinetic proofreading scheme with tRNA selection and DNA replication as guiding biological examples. Our theoretical analysis therefore suggests that the selectivity mechanisms are always kinetically controlled.
All-time dynamics of continuous-time random walks on complex networks
(American Institute of Physics, 2013) Teimouri, Hamid; Kolomeisky, Anatoly B.
The concept of continuous-time random walks (CTRW) is a generalization of ordinary random walk models, and it is a powerful tool for investigating a broad spectrum of phenomena in natural, engineering, social, and economic sciences. Recently, several theoretical approaches have been developed that allowed to analyze explicitly dynamics of CTRW at all times, which is critically important for understanding mechanisms of underlying phenomena. However, theoretical analysis has been done mostly for systems with a simple geometry. Here we extend the original method based on generalized master equations to analyze all-time dynamics of CTRWmodels on complex networks. Specific calculations are performed for models on lattices with branches and for models on coupled parallelchain lattices. Exact expressions for velocities and dispersions are obtained. Generalized fluctuations theorems for CTRW models on complex networks are discussed.
Analysis of Cooperative Behavior in Multiple Kinesins Motor Protein Transport by Varying Structural and Chemical Properties
(Springer, 2013) Uppulury, Karthik; Efremov, Artem K.; Driver, Jonathan W.; Jamison, D. Kenneth; Diehl, Michael R.; Kolomeisky, Anatoly B.
Intracellular transport is a fundamental biological process during which cellular materials are driven by enzymatic molecules called motor proteins. Recent optical trapping experiments and theoretical analysis have uncovered many features of cargo transport by multiple kinesin motor protein molecules under applied loads. These studies suggest that kinesins cooperate negatively under typical transport conditions, although some productive cooperation could be achieved under higher applied loads. However, the microscopic origins of this complex behavior are still not well understood. Using a discrete-state stochastic approach we analyze factors that affect the cooperativity among kinesin motors during cargo transport. Kinesin cooperation is shown to be largely unaffected by the structural and mechanical parameters of a multiple motor complex connected to a cargo, but much more sensitive to biochemical parameters affecting motor-filament affinities. While such behavior suggests the net negative cooperative responses of kinesins will persist across a relatively wide range of cargo types, it is also shown that the rates with which cargo velocities relax in time upon force perturbations are influenced by structural factors that affect the free energies of and load distributions within a multiple kinesin complex. The implications of these later results on transport phenomena where loads change temporally, as in the case of bidirectional transport, are discussed.
Anomalous Dense Liquid Condensates Host the Nucleation of Tumor Suppressor p53 Fibrils
(Cell Press, 2019) Safari, Mohammad S.; Wang, Zhiqing; Tailor, Kunaal; Kolomeisky, Anatoly B.; Conrad, Jacinta C.; Vekilov, Peter G.
About half of human cancers are associated with mutations of the tumor suppressor p53. Gained oncogenic functions of the mutants have been related to aggregation behaviors of wild-type and mutant p53. The thermodynamic and kinetic mechanisms of p53 aggregation are poorly understood. Here we find that wild-type p53 forms an anomalous liquid phase. The liquid condensates exhibit several behaviors beyond the scope of classical phase transition theories: their size, ca. 100 nm, is independent of the p53 concentration and decoupled from the protein mass held in the liquid phase. Furthermore, the liquid phase lacks constant solubility. The nucleation of p53 fibrils deviates from the accepted mechanism of sequential association of single solute molecules. We find that the liquid condensates serve as pre-assembled precursors of high p53 concentration that facilitate fibril assembly. Fibril nucleation hosted by precursors represents a novel biological pathway, which opens avenues to suppress protein fibrillation in aggregation diseases.
Asymmetry of forward/backward transition times as a non-equilibrium measure of complexity of microscopic mechanisms
(AIP, 2020) Shin, Jaeoh; Kolomeisky, Anatoly B.
Bacteria-Specific Feature Selection for Enhanced Antimicrobial Peptide Activity Predictions Using Machine-Learning Methods
(American Chemical Society, 2023) Teimouri, Hamid; Medvedeva, Angela; Kolomeisky, Anatoly B.; Center for Theoretical Biological Physics
There are several classes of short peptide molecules, known as antimicrobial peptides (AMPs), which are produced during the immune responses of living organisms against various infections. In recent years, substantial progress has been achieved in applying machine-learning methods to predict the activities of AMPs against bacteria. In most investigated cases, however, the outcome is not bacterium-specific since the specific features of bacteria, such as chemical composition and structure of membranes, are not considered. To overcome this problem, we developed a new computational approach that allowed us to train several supervised machine-learning models using a specific set of data associated with peptides targeting E. coli bacteria. LASSO regression and Support Vector Machine techniques have been utilized to select, among more than 1500 physicochemical descriptors, the most important features that can be used to classify a peptide as antimicrobial or ineffective against E. coli. We then performed the classification of active versus inactive AMPs using the Support Vector classifiers, Logistic Regression, and Random Forest methods. This computational study allows us to make recommendations of how to design more efficient antibacterial drug therapies.
Beyond Sequence: Internucleosomal Interactions Dominate Array Assembly
(American Chemical Society, 2022) Wang, Yaqing; Stormberg, Tommy; Hashemi, Mohtadin; Kolomeisky, Anatoly B.; Lyubchenko, Yuri L.; Center for Theoretical Biological Physics
The organization of the nucleosome array is a critical component of the chromatin assembly into higher order structure as well as its function. Here, we investigated the contributions of the DNA sequence and internucleosomal interactions on the organization of the nucleosomal arrays in compact structures using atomic force microscopy. We assembled nucleosomes on DNA substrates allowing for the formation of tetranucleosomes. We found that nucleosomes are capable of close positioning with no discernible space between them, even in the case of assembled dinucleosomes. This morphology of the array is in contrast with that observed for arrays assembled with repeats of the nucleosome positioning motifs separated by uniform spacers. Simulated assembly of tetranucleosomes by random placement along the substrates revealed that nucleosome array compaction is promoted by the interaction of the nucleosomes. We developed a theoretical model to account for the role of DNA sequence and internucleosomal interactions in the formation of the nucleosome structures. These findings suggest that, in the chromatin assembly, the affinity of the nucleosomes to the DNA sequence and the strengths of the internucleosomal interactions are the two major factors defining the compactness of the chromatin.
Bulk induced phase transition in driven diffusive systems
(Nature Publishing Group, 2014) Wang, Yu-Qing; Jiang, Rui; Kolomeisky, Anatoly B.; Hu, Mao-Bin
This paper studies a weakly and asymmetrically coupled three-lane driven diffusive system. A non-monotonically changing density profile in the middle lane has been observed. When the extreme value of the density profile reaches ρ = 0.5, a bulk induced phase transition occurs which exhibits a shock and a continuously and smoothly decreasing density profile which crosses ρ = 0.5 upstream or downstream of the shock. The existence of double shocks has also been observed. A mean-field approach has been used to interpret the numerical results obtained by Monte Carlo simulations. The current minimization principle has excluded the occurrence of two or more bulk induced shocks in the general case of nonzero lane changing rates.
Can we understand the mechanisms of tumor formation by analyzing dynamics of cancer initiation?
(IOP Publishing, 2022) Teimouri, Hamid; Kolomeisky, Anatoly B.; Center for Theoretical Biological Physics
Cancer is a collection of related genetic diseases exhibiting uncontrolled cell growth that interferes with normal functioning of human organisms. It results from accumulation of unfavorable mutations in tissues. While the biochemical picture of how cancer appears is known, the molecular mechanisms of tumor formation remain not fully understood despite tremendous efforts of researchers in multiple fields. New approaches for investigating cancer are constantly sought. In this paper, we discuss a powerful method of clarifying better a more microscopic picture of cancer by analyzing the dynamics of tumor formation. Using physics- and chemistry-inspired discrete-state stochastic description of cancer initiation, it is shown how the mechanisms of tumor formation can be uncovered. This approach is suggested as a powerful new physical-chemical tool for a better understanding of complex processes associated with cancer.
Collective dynamics of processive cytoskeletal motors
(Royal Society of Chemistry, 2016) McLaughlin, R. Tyler; Diehl, Michael R.; Kolomeisky, Anatoly B.; Center for Theoretical Biological Physics
Major cellular processes are supported by various biomolecular motors that usually operate together as teams. We present an overview of the collective dynamics of processive cytokeletal motor proteins based on recent experimental and theoretical investigations. Experimental studies show that multiple motors function with different degrees of cooperativity, ranging from negative to positive. This effect depends on the mechanical properties of individual motors, the geometry of their connections, and the surrounding cellular environment. Theoretical models based on stochastic approaches underline the importance of intermolecular interactions, the properties of single motors, and couplings with cellular medium in predicting the collective dynamics. We discuss several features that specify the cooperativity in motor proteins. Based on this approach a general picture of collective dynamics of motor proteins is formulated, and the future directions and challenges are discussed.
Cooperative mechanisms in coupled motor proteins transport
(2012) Uppulury, Karthik; Kolomeisky, Anatoly B.
Subcellular cargos are transported by enzyme molecules called molecular motors by using the chemical energy from hydrolysis of ATP and performing mechanical work in non-equilibrium. Certain motors tread on cytoskeleton structures i.e. microtubules and actin filaments in a linear manner. Due to the polarity of the cytoskeleton structures the motors can accomplish cellular transport along one direction. Cargos often rely upon the collective action of more than one motor to transport them in order to surmount the crowding and visco-elastic effects of the surrounding medium through higher force generation. To understand the mechanism of cargo transport by precisely two kinesin-1 motors a combination of experimental and theoretical approaches were employed. This thesis focuses on understanding the mechanism of transport by considering interactions between closely spaced motors on the microtubules. The main finding of this thesis is that motors under the influence of each other's interaction with microtubules do affect the cargo dynamics.
Cooperativity in Bacterial Membrane Association Controls the Synergistic Activities of Antimicrobial Peptides
(American Chemical Society, 2022) Nguyen, Thao N.; Teimouri, Hamid; Medvedeva, Angela; Kolomeisky, Anatoly B.; Center for Theoretical Biological Physics
Antimicrobial peptides (AMPs), or defence peptides, are compounds naturally produced during immune responses of living organisms against bacterial infections that are currently actively considered as promising alternatives to antibiotics. Recent experimental studies uncovered that in many situations, combinations of different AMPs are much more successful in eliminating the bacterial pathogens than single peptide species. However, the microscopic origin of such synergistic activities remains not fully understood. We present and investigate a possible mechanism of synergy between AMPs. It is based on the idea that due to inter-molecular interactions, the presence of an AMP of one type stimulates the association of an AMP of another type, and this accelerates the overall association to the membrane, eventually killing the bacteria. This approach allows us to fully quantify the synergistic activities of AMPs, and it is successfully applied for several experimental systems. It is found that strong cooperativity can be achieved for relatively weak inter-molecular interactions, suggesting that the application of combinations of AMPs can be further rationally optimized to make it a powerful antibacterial treatment.
Coupled simple exclusion process models
(2009) Tsekouras, Konstantinos; Kolomeisky, Anatoly B.
This study investigates problems in the overall context of intracellular particle transport using coupled simple exclusion processes to construct mathematical models of systems under consideration. Nonequilibrium statistical mechanics and cluster mean-field theory are used to analytically solve the model steady state and derive phase diagrams and quantities characteristic of transport such as average density and entrance/bulk/exit currents. All results are supported by extensive Monte-Carlo simulations. Four systems are investigated, namely: A system where kinesin motor proteins jump between microtubule tracks due to a single-point inhomogeneity; a system where transport of kinesins on a microtubule is interrupted by a diffusive compartment; a system where kinesin transport on a microtubule is coupled to the aqueous medium surrounding it; and finally a system where dyneins are transported on two protofilaments linked to each other at every site.
Crowding on DNA in Protein Search for Targets
(American Chemical Society, 2016) Shvets, Alexey A.; Kolomeisky, Anatoly B.; Center for Theoretical Biological Physics
Proteins searching and recognizing specific sites on DNA is required for initiating all major biological processes. While the details of the protein search for targets on DNA in purified in vitro systems are reasonably well understood, the situation in real cells is much less clear. The presence of other types of molecules on DNA should prevent reaching the targets, but experiments show that, surprisingly, the molecular crowding on DNA influences the search dynamics much less than expected. We develop a theoretical method that allowed us to clarify the mechanisms of the protein search on DNA in the presence of crowding. It is found that the dimensionality of the search trajectories specifies whether the crowding will affect the target finding. For 3D search pathways it is minimal, while the strongest effect is for 1D search pathways when the crowding particle can block the search. In addition, for 1D search we determined that the critical parameter is a mobility of crowding agents: highly mobile molecules do not affect the search dynamics, while the slow particles can significantly slow down the process. Physical-chemical explanations of the observed phenomena are presented. Our theoretical predictions thus explain the experimental observations, and they are also supported by extensive numerical simulations.
Current-Generating Double-Layer Shoe with a Porous Sole: Ion Transport Matters
(American Chemical Society, 2017) Kornyshev, Alexei A.; Twidale, Rebecca M.; Kolomeisky, Anatoly B.; Center for Theoretical Biological Physics
Generating electrical current from mechanically forced variation of the contact area of electrode/electrolyte interface underpins one of the scenarios of harvesting electrical current from walking. We develop here theory of an electrical shoe with a porous sole with an account of both convection of the liquid electrolyte under pressure and ion migration with transmission-line-type charging of electrical double layer at the pore walls. We show here that ion transport limitations can dramatically reduce the generated current and power density. The developed theory describes the time dependence of the generated current and reveals its dependence on the main operation parameters, the amplitudes of oscillating pressure and frequency, in relation to the system parameters.
Development of morphogen gradient: The role of dimension and discreteness
(AIP Publishing, 2014) Teimouri, Hamid; Kolomeisky, Anatoly B.; Center for Theoretical Biological Physics
The fundamental processes of biological development are governed by multiple signaling molecules that create non-uniform concentration profiles known as morphogen gradients. It is widely believed that the establishment of morphogen gradients is a result of complex processes that involve diffusion and degradation of locally produced signaling molecules. We developed a multi-dimensional discrete-state stochastic approach for investigating the corresponding reaction-diffusion models. It provided a full analytical description for stationary profiles and for important dynamic properties such as local accumulation times, variances, and mean first-passage times. The role of discreteness in developing of morphogen gradients is analyzed by comparing with available continuum descriptions. It is found that the continuum models prediction about multiple time scales near the source region in two-dimensional and three-dimensional systems is not supported in our analysis. Using ideas that view the degradation process as an effective potential, the effect of dimensionality on establishment of morphogen gradients is also discussed. In addition, we investigated how these reaction-diffusion processes are modified with changing the size of the source region.
Development of Morphogen Gradients with Spatially Varying Degradation Rates
(American Chemical Society, 2016) Teimouri, Hamid; Bozorgui, Behnaz; Kolomeisky, Anatoly B.; Center for Theoretical Biological Physics
Successful biological development via spatial and temporal regulations of cell differentiation relies on the action of multiple signaling molecules that are known as morphogens. It is now well established that biological signaling molecules create nonuniform concentration profiles, called morphogen gradients, that activate different genes, leading to patterning in the developing organisms. The current view of the formation of morphogen gradients is that it is a result of complex reaction–diffusion processes that include production, diffusion, and degradation of signaling molecules. Recent studies also suggest that the degradation of morphogens is a critically important step in the whole process. We develop a theoretical model that allows us to investigate the role of a spatially varying degradation in the formation of morphogen gradients. Our analysis shows that the spatial inhomogeneities in degradation might strongly influence the dynamics of formation of signaling profiles. Physical–chemical mechanisms of the underlying processes are discussed.

Browsing by Author "Kolomeisky, Anatoly B."

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