In this autobiography, I describe my childhood and early education and summarize structural biology research in nucleic acids and proteins and my work with the Protein Data Bank.
I review recent advances in nonequilibrium thermodynamics of biochemical networks, organized around two central questions. First, why is free energy dissipation essential for enabling or enhancing biological function? Second, how do energetic costs constrain functional performance? Using several representative systems—beginning with the classical kinetic proofreading mechanism and extending to more recent examples such as accurate sensory adaptation, ultrasensitive responses, and synchronization of biochemical oscillators—I show that this framework not only provides new insights into the molecular mechanisms underlying these diverse processes but also reveals the general thermodynamic principles that govern their biological functions. I highlight the characteristic signatures of nonequilibrium behavior and the emergence of fundamental energy–performance trade-offs. This review strives to present the framework pedagogically and with sufficient technical detail to enable theory-inclined biophysicists to apply it to their own systems of interest. I conclude by proposing a nonequilibrium thermodynamic law for living systems and outlining promising directions for extending this theoretical approach to an even broader range of biological phenomena.
Since the beginning of this century, the emergence of systems biology, driven by technological, informatic, and theoretical advances, has led to an unprecedented generation of data and information about biological systems at multiple levels of organization. We now have access not only to components of living systems but also to some of the underlying principles governing their organization within networks. This review focuses on the systems biology of aging, metabolism, and mitochondria, along with the integration of experimental and computational systems biology approaches as applied to multilayered biological networks, spanning from the molecular-subcellular to the whole organism. Sections 2 and 3 provide an overview of the insights gained from systems biology and multi-omics approaches as applied to aging and metabolism. Using the spatiotemporal dynamics of biological networks as a unifying thread, Sections 4 and 5 explore how systems biology and current methods can leverage the understanding of complex biological phenomena through integrated experimental-computational strategies, utilizing iterative, verification-validation loops between experiments and models. Section 6 concludes by highlighting the autonomously dynamic, self-organizing, and self-regulating integrative nature of living systems and the need to address these properties at the emerging convergence of biology, medicine, physics, and powerful computational technologies that include artificial intelligence.
Photosynthesis, the biological process of converting light energy into chemical energy, involves light harvesting, charge separation and electron transport, proton translocation, ATP synthesis, and carbon fixation, among other processes. Adjacent photosynthetic complexes may assemble into supramolecular complexes to couple and regulate their functions. Here, we review the progress of structural biology studies of photosynthetic supramolecular complexes, such as those that have light-harvesting complexes assembled with photosystem II (PSII) or photosystem I (PSI), both PSII and PSI, or bacterial reaction center complexes. The intricate architectures of the NADH dehydrogenase-like (NDH) complex and PSI-NDH supercomplex, revealed through cryo-electron microscopy studies, provide crucial frameworks for understanding the molecular mechanisms of cyclic electron flow in cyanobacteria and plants. Furthermore, structural studies have also yielded detailed insights into the assembly and repair of PSII, regulation of ATP synthase, and carbon fixation. The review concludes with a summary of the emerging directions of structural biology studies of photosynthetic supramolecular complexes.
Voltage-dependent anion channels (VDACs) of the outer mitochondrial membrane carry out bidirectional flux of metabolites and ions and serve as the first line of communication between the cytosol and mitochondria. They are now recognized as indispensable for mitochondrial function and cellular homeostasis, mitochondria-endoplasmic reticulum communication, lipid and cholesterol biogenesis, Ca2+ homeostasis, and mitochondria-mediated apoptosis. The unique structural features of VDACs are also important in redox regulation. VDAC dysregulation by interaction with amyloid-β, α-synuclein, Tau, or tubulin can lead to neurodegeneration. Here, we provide insights into the structures, isoform-specific molecular functions, cellular interactome, variations, and unique regulatory elements of VDACs and their direct implications for widespread burdens like cancer and neurodegeneration in humans. We discuss how deducing isoform-specific structure-function studies of VDACs has the potential for successful development of next-generation diagnostics-guided therapeutics.
