Abstract: Biomolecular machinery are mainly nanoscale protein complexes that perform cyclic functional cycles driven by chemical free energy in the cell. Despite of significant noises and fluctuations from cellular environments, highly efficient and/or accurate functional performances are often achieved in these molecular complexes, which motivate us for understanding the underlying physics that guide molecular evolution/design principles and biomedical applications. Implementing physical modeling and simulation from atomic to coarse-grained level, along with molecular mechanics, statistic physics, and stochastic kinetic/dynamics methods, we have recently probed gene transcription machinery in minimal functional modules. In particular, we investigated transcription factor domain protein diffusional search along DNA for specific target sequences, viral RNA polymerase as the core molecular engine with mechano-chemical and fidelity control, and DNA supercoiling as mechanical feedback in regulating bacterial transcription and genetic noise production. Multi-scale modeling and cross-scale computational platforms are highlighted to reveal physical mechanisms of the molecular machines from microscopic to mesoscopic regime.