Abstract: Protein conformational changes due to either intrinsic fluctuations or ligand-induced perturbations are essential in mediating functional molecular mechanics supporting all forms of life in nature. In this talk, I will first present the evidence revealing the robustness of low-frequency dynamics characterized by “structural errors” of NMR structures and simple network models. Then, I will talk about our latest work where we formulated a set of linear response theories (LRT), both time-dependent/-independent that describe the functional conformational changes of proteins as being triggered by external perturbations (ligand-induced forces) in accord with the inclinations of its intrinsic dynamics (unperturbed fluctuation covariance). Using the theories, we are able to study the time-resolved, mechanical signal propagations inside the myoglobin molecule upon carbon monoxide binding, and derive time constants of the molecular response (ranging from hundreds of femtoseconds to a few tens of picoseconds) which agree with those characterized by UV Resonance Raman (UVRR) spectrometry. I will also give a personal view on how lock&key and induced-fit can be understood in the framework of LRT.