The Mystery of Physics 101

Hertz and his scientific contemporaries correctly viewed conceptual disharmony as the inevitable product of the evolutionary manner in which an initial descriptive practice gradually enlarges its applicational outreach, pragmatically guided by the discovery of fresh opportunities for calculating results in a useful manner. As a side effect of this increasing accumulation of technique, component words will become naturally pulled into subtly different forms of localized referential attachment. These discordant alignments create difficulties when a straightforward exposition of “fundamental principle” is wanted, as arises within an elementary class in classical mechanics (this is the “mystery” of the chapter’s title). Hertz, in particular, noticed that the word “force” behaves in a diverging manner, according to the comparative scale size of the object under consideration. This structural insight is crucial to unraveling the resulting conceptual tensions, but the axiomatic corrective that Hertz proposed leads to very unfortunate results, because such a scheme must artificially choose which of these usages of “force” should be favored as “primary.” Nonetheless, Hertz’s faulty presumption that axiomatics represents the proper vehicle for rectifying conceptual tangles of this character has turned into a widely accepted methodological dogma. It constitutes the foundational basis of the theory T thinking of which this book complains. Again the finer details outlined in this chapter are not essential for following the main argument of this work, but they nicely illuminate its motivational background.

Structural insight on the mechanism of an electron-bifurcating [FeFe] hydrogenase

Electron-bifurcation is a fundamental energy conservation mechanism in nature. The electron-bifurcating [FeFe] hydrogenase from Thermotoga maritima (HydABC) requires both NADH and ferredoxin to reduce protons generating hydrogen. The mechanism of electron-bifurcation in HydABC remains enigmatic primarily due to the lack of structural information. Here, we present a 2.3 Å electron cryo-microscopy structure of HydABC. The structure is a heterododecamer composed of two independent ‘halves’ each made of two strongly interacting HydABC heterotrimers electrically connected via a [4Fe-4S] cluster. A central electron transfer pathway connects the active sites for NADH oxidation and proton reduction. Symmetry expansion identified two conformations of a flexible iron-sulfur cluster domain: a “closed bridge” and an “open bridge” conformation, where a Zn2+ site may act as a “hinge” allowing domain movement. Based on these structural revelations, we propose two new mechanisms of electron-bifurcation in HydABC.

Structural Insight into the Binding of TGIF1 to SIN3A PAH2 Domain through a C-Terminal Amphipathic Helix

TGIF1 is a transcriptional repressor playing crucial roles in human development and function and is associated with holoprosencephaly and various cancers. TGIF1-directed transcriptional repression of specific genes depends on the recruitment of corepressor SIN3A. However, to date, the exact region of TGIF1 binding to SIN3A was not clear, and the structural basis for the binding was unknown. Here, we demonstrate that TGIF1 utilizes a C-terminal domain (termed as SIN3A-interacting domain, SID) to bind with SIN3A PAH2. The TGIF1 SID adopts a disordered structure at the apo state but forms an amphipathic helix binding into the hydrophobic cleft of SIN3A PAH2 through the nonpolar side at the holo state. Residues F379, L382 and V383 of TGIF1 buried in the hydrophobic core of the complex are critical for the binding. Moreover, homodimerization of TGIF1 through the SID and key residues of F379, L382 and V383 was evidenced, which suggests a dual role of TGIF1 SID and a correlation between dimerization and SIN3A-PAH2 binding. This study provides a structural insight into the binding of TGIF1 with SIN3A, improves the knowledge of the structure–function relationship of TGIF1 and its homologs and will help in recognizing an undiscovered SIN3A-PAH2 binder and developing a peptide inhibitor for cancer treatment.