Boolean network-based model of the Bcl-2 family mediated MOMP regulation

Mitochondrial outer membrane permeabilization (MOMP) is one of the most important points, in majority of apoptotic signaling cascades. Decision mechanism controlling whether the MOMP occurs or not, is formed by an interplay between members of the Bcl-2 family. To understand the role of individual members of this family within the MOMP regulation, we constructed a boolean network-based mathematical model of interactions between the Bcl-2 proteins. Results of computational simulations reveal the existence of the potentially malign configurations of activities of the Bcl-2 proteins, blocking the occurrence of MOMP, independently of the incoming stimuli. Our results suggest role of the antiapoptotic protein Mcl-1 in relation to these configurations. We demonstrate here, the importance of the Bid and Bim according to activation of effectors Bax and Bak, and the irreversibility of this activation. The model further shows the distinct requirements for effectors activation, where the antiapoptic protein Bcl-w is seemingly a key factor preventing the Bax activation. We believe that this work may help to describe the functioning of the Bcl-2 regulation of MOMP better, and hopefully provide some contribution regarding the anti-cancer drug development research

Roadmap for Computer-Aided Modeling of Theranostics and Related Nanosystems

Detailed understanding of the interactions of novel metal-containing nanoparticles with biological membranes, macromolecules and other molecular targets of the living cell is crucial for the elucidation of the biological actions of such functionalized nanosystems. We present here the construction and modeling of thiolate-protected gold clusters and the prediction of their static and dynamic properties

Interaction of a new antiviral and antitumor photosensitizer hypericin with human serum albumin: molecular modeling study

Molecular modeling has been employed to study the interaction of hypericin (Hyp) with human serum albumin (HSA). The structural model for Hyp/HSA complex is presented. Our results indicate that Hyp is bound in II A subdomain of HSA close to the tryptophan 214 (Trp214) (distance 5.12 Å between the centers of masses). In the presented model the carbonyl group of Hyp is hydrogen bonded to the Asn458. Another two candidates for hydrogen bonds have been identified between the bay-region hydroxyl group of Hyp and the carbonyl group of the Trp214 peptidic link and between the peri-region hydroxyl group of Hyp and Asn458 carbonyl group

Roadmap for Computer-Aided Modeling of Theranostics and Related Nanosystems

Detailed understanding of the interactions of novel metal-containing nanoparticles with biological membranes, macromolecules and other molecular targets of the living cell is crucial for the elucidation of the biological actions of such functionalized nanosystems. We present here the construction and modeling of thiolate-protected gold clusters and the prediction of their static and dynamic properties

Roadmap for Computer-Aided Modeling of Theranostics and Related Nanosystems

Detailed understanding of the interactions of novel metal-containing nanoparticles with biological membranes, macromolecules and other molecular targets of the living cell is crucial for the elucidation of the biological actions of such functionalized nanosystems. We present here the construction and modeling of thiolate-protected gold clusters and the prediction of their static and dynamic properties

The mathematical model of the Bcl-2 family mediated MOMP regulation can perform a non-trivial pattern recognition.

Interactions between individual members of the B-cell lymphoma 2 (Bcl-2) family of proteins form a regulatory network governing mitochondrial outer membrane permeabilization (MOMP). Bcl-2 family initiated MOMP causes release of the inter-membrane pro-apoptotic proteins to cytosol and creates a cytosolic environment suitable for the executionary phase of apoptosis. We designed the mathematical model of this regulatory network where the synthesis rates of the Bcl-2 family members served as the independent inputs. Using computational simulations, we have then analyzed the response of the model to up-/downregulation of the Bcl-2 proteins. Under several assumptions, and using estimated reaction parameters, a non-linear stimulus-response emerged, whose characteristics are associated with bistability and switch-like behavior. Interestingly, using the principal component analysis (PCA) we have shown that the given model of the Bcl-2 family interactions classifies the random combinations of inputs into two distinct classes, and responds to these by one of the two qualitatively distinct outputs. As we showed, the emergence of this behavior requires specific organization of the interactions between particular Bcl-2 proteins

Theoretical Analysis of the Excited State Properties of Wybutine: A Natural Probe for Transfer RNA Dynamics

Abstract: We have theoretically characterized the ground state and the excited state properties of wybutine, a naturally fluorescent modified base occuring in tRNAs, using configuration interaction singles (CIS) and time dependent density functional (TDDFT) methods. Both gas phase excited state properties and solvent effects, modelled through Onsager reaction field method, were considered. In addition to vertical excitation energies, the fluorescence transitions were calculated, based on S1 equilibrium geometry optimized at CIS level. Our computations show encouraging agreement with known experimental data either directly (TDDFT) or after applying empirical scaling (CIS). The fluorescence Stokes’ shift for the S0 Ã S1 transition is computed taking into account the contributions from both intramolecular and solvent reorganization processes. The results suggest that intramolecular relaxation of the S1 state accounts for the major part of the magnitude of the Stokes’ shift, while the role of solvent reorganization seems to be of less importance