Optimal pathways control fixation of multiple mutations during cancer initiation
We present a new theoretical framework of analyzing the cancer initiation dynamics by exploring the properties of effective free-energy landscape of the process. It is argued that although there are many possible pathways for the fixation of all mutations in the system, there are only few dominating pathways on the road to tumor formation. The theoretical approach is explicitly tested in the system with only two mutations using analytical calculations and Monte Carlo computer simulations. Excellent agreement with theoretical predictions is found for a large range of parameters, supporting our hypothesis and allowing us to ...
Source: Biophysical Journal - May 15, 2022 Category: Physics Authors: Hamid Teimouri Cade Spaulding Anatoly B Kolomeisky Source Type: research

Best practice for improved accuracy: a critical reassessment of van't Hoff analysis of melt curves
Biophys J. 2022 May 10:S0006-3495(22)00375-7. doi: 10.1016/j.bpj.2022.05.008. Online ahead of print.ABSTRACTBiomolecular thermodynamics, particularly for DNA, are frequently determined via van't Hoff analysis of optically-measured melt curves. Accurate and precise values of thermodynamic parameters are essential for the modelling of complex systems involving cooperative effects, such as RNA tertiary structure and DNA origami because the uncertainties associated with each motif in a folding energy landscape can compound, significantly reducing the power of predictive models. We follow the sources of uncertainty as they prop...
Source: Biophysical Journal - May 13, 2022 Category: Physics Authors: Jacob M Majikes Michael Zwolak J Alexander Liddle Source Type: research

Bending stiffness characterization of Bacillus subtilis' flagellar filament
Biophys J. 2022 May 11:S0006-3495(22)00377-0. doi: 10.1016/j.bpj.2022.05.010. Online ahead of print.ABSTRACTThe filament of a bacterial flagellum is a tube-like organelle made of single protein - flagellin, and assembled into multiple polymorphic forms. The filament can be further discretized into four subunit domains (D0, D1, D2 and D3) along the radial direction. However, it remains unclear which subunit domain plays an important role in regulating the rigidity of the filament. In this article, we address how the absence of two outer subunit domains (D2 and D3) affects the bending stiffness of the bacterium B. subtilis' ...
Source: Biophysical Journal - May 13, 2022 Category: Physics Authors: Xinhui Shen Phu N Tran Benjamin Z Tay None Marcos Source Type: research

Best practice for improved accuracy: a critical reassessment of van't Hoff analysis of melt curves
Biophys J. 2022 May 10:S0006-3495(22)00375-7. doi: 10.1016/j.bpj.2022.05.008. Online ahead of print.ABSTRACTBiomolecular thermodynamics, particularly for DNA, are frequently determined via van't Hoff analysis of optically-measured melt curves. Accurate and precise values of thermodynamic parameters are essential for the modelling of complex systems involving cooperative effects, such as RNA tertiary structure and DNA origami because the uncertainties associated with each motif in a folding energy landscape can compound, significantly reducing the power of predictive models. We follow the sources of uncertainty as they prop...
Source: Biophysical Journal - May 13, 2022 Category: Physics Authors: Jacob M Majikes Michael Zwolak J Alexander Liddle Source Type: research

Bending stiffness characterization of Bacillus subtilis' flagellar filament
Biophys J. 2022 May 11:S0006-3495(22)00377-0. doi: 10.1016/j.bpj.2022.05.010. Online ahead of print.ABSTRACTThe filament of a bacterial flagellum is a tube-like organelle made of single protein - flagellin, and assembled into multiple polymorphic forms. The filament can be further discretized into four subunit domains (D0, D1, D2 and D3) along the radial direction. However, it remains unclear which subunit domain plays an important role in regulating the rigidity of the filament. In this article, we address how the absence of two outer subunit domains (D2 and D3) affects the bending stiffness of the bacterium B. subtilis' ...
Source: Biophysical Journal - May 13, 2022 Category: Physics Authors: Xinhui Shen Phu N Tran Benjamin Z Tay None Marcos Source Type: research

Best practice for improved accuracy: a critical reassessment of van't Hoff analysis of melt curves
Biophys J. 2022 May 10:S0006-3495(22)00375-7. doi: 10.1016/j.bpj.2022.05.008. Online ahead of print.ABSTRACTBiomolecular thermodynamics, particularly for DNA, are frequently determined via van't Hoff analysis of optically-measured melt curves. Accurate and precise values of thermodynamic parameters are essential for the modelling of complex systems involving cooperative effects, such as RNA tertiary structure and DNA origami because the uncertainties associated with each motif in a folding energy landscape can compound, significantly reducing the power of predictive models. We follow the sources of uncertainty as they prop...
Source: Biophysical Journal - May 13, 2022 Category: Physics Authors: Jacob M Majikes Michael Zwolak J Alexander Liddle Source Type: research

Biophysical insights into OR2T7: Investigation of a potential prognostic marker for glioblastoma
This study provides the theoretical basis for further experimental investigation required to confirm that the D125V mutation in OR2T7 is not a passenger mutation. With validation, the above mutation could represent an important prognostic marker and a potential therapeutic target for glioblastoma.PMID:35538663 | DOI:10.1016/j.bpj.2022.05.009 (Source: Biophysical Journal)
Source: Biophysical Journal - May 11, 2022 Category: Physics Authors: A K Sharp D Newman G Libonate M B Stern D R Bevan A M Brown R Anandakrishnan Source Type: research

Identification of Core Allosteric Sites through Temperature- and Nucleus-Invariant Chemical Shift Covariance
Biophys J. 2022 May 9:S0006-3495(22)00371-X. doi: 10.1016/j.bpj.2022.05.004. Online ahead of print.ABSTRACTAllosteric regulation is essential to control biological function. In addition, allosteric sites offer a promising venue for selective drug targeting. However, accurate mapping of allosteric sites remains challenging since allostery relies on often subtle, yet functionally relevant, structural and dynamical changes. A viable approach proposed to overcome such challenge is the chemical shift covariance analysis (CHESCA). Although CHESCA offers an exhaustive map of allosteric networks, it is critical to define the core ...
Source: Biophysical Journal - May 11, 2022 Category: Physics Authors: Hebatallah Mohamed Ubaidullah Baryar Amir Bashiri Rajeevan Selvaratnam Bryan VanSchouwen Giuseppe Melacini Source Type: research

Simulations of Cross-Amyloid Aggregation of Amyloid- β and Islet Amyloid Polypeptide Fragments
Biophys J. 2022 May 9:S0006-3495(22)00374-5. doi: 10.1016/j.bpj.2022.05.007. Online ahead of print.ABSTRACTAmyloid-beta (Aβ) and islet amyloid polypeptide (IAPP) are small peptides, classified as amyloids, that have the potential to self-assemble and form cytotoxic species, such as small soluble oligomers and large insoluble fibrils. The formation of Aβ aggregates facilitates the progression of Alzheimer's disease (AD), while IAPP aggregates induce pancreatic β-cell apoptosis, leading to exacerbation of Type 2 diabetes (T2D). Cross-amyloid interactions between Aβ and IAPP have been described both in vivo and in vitro, ...
Source: Biophysical Journal - May 11, 2022 Category: Physics Authors: Grant Kawecki Kelsie M King Nicholas Cramer David R Bevan Anne M Brown Source Type: research

Biophysical insights into OR2T7: Investigation of a potential prognostic marker for glioblastoma
This study provides the theoretical basis for further experimental investigation required to confirm that the D125V mutation in OR2T7 is not a passenger mutation. With validation, the above mutation could represent an important prognostic marker and a potential therapeutic target for glioblastoma.PMID:35538663 | DOI:10.1016/j.bpj.2022.05.009 (Source: Biophysical Journal)
Source: Biophysical Journal - May 11, 2022 Category: Physics Authors: A K Sharp D Newman G Libonate M B Stern D R Bevan A M Brown R Anandakrishnan Source Type: research

Identification of Core Allosteric Sites through Temperature- and Nucleus-Invariant Chemical Shift Covariance
Biophys J. 2022 May 9:S0006-3495(22)00371-X. doi: 10.1016/j.bpj.2022.05.004. Online ahead of print.ABSTRACTAllosteric regulation is essential to control biological function. In addition, allosteric sites offer a promising venue for selective drug targeting. However, accurate mapping of allosteric sites remains challenging since allostery relies on often subtle, yet functionally relevant, structural and dynamical changes. A viable approach proposed to overcome such challenge is the chemical shift covariance analysis (CHESCA). Although CHESCA offers an exhaustive map of allosteric networks, it is critical to define the core ...
Source: Biophysical Journal - May 11, 2022 Category: Physics Authors: Hebatallah Mohamed Ubaidullah Baryar Amir Bashiri Rajeevan Selvaratnam Bryan VanSchouwen Giuseppe Melacini Source Type: research

Simulations of Cross-Amyloid Aggregation of Amyloid- β and Islet Amyloid Polypeptide Fragments
Biophys J. 2022 May 9:S0006-3495(22)00374-5. doi: 10.1016/j.bpj.2022.05.007. Online ahead of print.ABSTRACTAmyloid-beta (Aβ) and islet amyloid polypeptide (IAPP) are small peptides, classified as amyloids, that have the potential to self-assemble and form cytotoxic species, such as small soluble oligomers and large insoluble fibrils. The formation of Aβ aggregates facilitates the progression of Alzheimer's disease (AD), while IAPP aggregates induce pancreatic β-cell apoptosis, leading to exacerbation of Type 2 diabetes (T2D). Cross-amyloid interactions between Aβ and IAPP have been described both in vivo and in vitro, ...
Source: Biophysical Journal - May 11, 2022 Category: Physics Authors: Grant Kawecki Kelsie M King Nicholas Cramer David R Bevan Anne M Brown Source Type: research

Influence of effective polarization on ion and water interactions within a biomimetic nanopore
Biophys J. 2022 May 7:S0006-3495(22)00373-3. doi: 10.1016/j.bpj.2022.05.006. Online ahead of print.ABSTRACTInteractions between ions and water at hydrophobic interfaces within ion channels and nanopores are suggested to play a key role in the movement of ions across biological membranes. Previous molecular dynamics (MD) simulations have shown that anion affinity for aqueous/hydrophobic interfaces can be markedly influenced by including polarization effects through an electronic continuum correction (ECC). Here, we designed a model biomimetic nanopore to imitate the polar pore openings and hydrophobic gating regions found i...
Source: Biophysical Journal - May 9, 2022 Category: Physics Authors: Linda X Phan Charlotte I Lynch Jason Crain Mark S P Sansom Stephen J Tucker Source Type: research

Single-molecule studies reveal method for tuning the heterogeneous activity of Alkaline Phosphatase
Biophys J. 2022 May 7:S0006-3495(22)00372-1. doi: 10.1016/j.bpj.2022.05.005. Online ahead of print.ABSTRACTSingle-molecule enzymology (SME) methods have enabled the observation of heterogeneous catalytic activities within a single enzyme population. Heterogenous activity is hypothesized to originate from conformational changes in the enzyme that result from changes in the local environment leading to catalytically-active substates. Here, we use SME to investigate the mechanisms of heterogenous activity exhibited by tissue nonspecific alkaline phosphatase (TNSALP), which reveals two subpopulations with different catalytic a...
Source: Biophysical Journal - May 9, 2022 Category: Physics Authors: Tal Gilboa Alana F Ogata Charles Reilly David R Walt Source Type: research

Influence of effective polarization on ion and water interactions within a biomimetic nanopore
Biophys J. 2022 May 7:S0006-3495(22)00373-3. doi: 10.1016/j.bpj.2022.05.006. Online ahead of print.ABSTRACTInteractions between ions and water at hydrophobic interfaces within ion channels and nanopores are suggested to play a key role in the movement of ions across biological membranes. Previous molecular dynamics (MD) simulations have shown that anion affinity for aqueous/hydrophobic interfaces can be markedly influenced by including polarization effects through an electronic continuum correction (ECC). Here, we designed a model biomimetic nanopore to imitate the polar pore openings and hydrophobic gating regions found i...
Source: Biophysical Journal - May 9, 2022 Category: Physics Authors: Linda X Phan Charlotte I Lynch Jason Crain Mark S P Sansom Stephen J Tucker Source Type: research