Discoveries in Biophysics through the Computational Microscope

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All-atom molecular dynamics simulations resolve the physical mechanisms underlying the dynamic function of biological macromolecules and serve today as a computational microscope. This microscope truly complements and goes hand-in-hand with experimental observation, though it has also made its own discoveries, for example, in studies of protein mechanics. Progress in developing the computational microscope was tied to advances in the size and time scale covered by molecular dynamics simulations: reaching the 100,000 atom and 10-ns scales in 2000 opened the field of in situ membrane protein simulations leading to the discovery of selectivity and gating in water and ion channels; reaching the million atom and μs-to-ms scales in 2010 resolved the actual folding pathways of 50-100 aa long proteins and of the control mechanisms in the ribosome, including the insertion of nascent proteins into a membrane. Recently, simulations have reached the 100 million atom and μs-to-ms scales permitting, in conjunction with multi-modal structural biology experiments, atomic-level images of the HIV capsid and its chemical interaction with host cell factors. Simulations now permit even the electronic-to-atomic level description of an entire photosynthetic membrane through a combination of various experiments with molecular dynamics simulations, quantum mechanical calculations and kinetic modeling. Culminating over four decades of investigation, the results have led to an atomic-level model of a spherical membrane, the photosynthetic chromatophore of purple bacteria, made of 20,000 lipids and 100 proteins with 3,000 co-factors. A movie based on the model reveals the step-by-step electronic- and atomic-level conversion of light energy into ATP synthesis. The lecture illustrates also the many-fold algorithmic advances in sampling, force evaluation, physical analysis, automated model construction, molecular graphics and experimental data analysis that were necessary to reach the present stage of computational microscopy.