The whole-cell simulation of cell metabolic processes under considering a variable-volume modelling framework has been reviewed to prove their advantages when building-up modular model structures that can reproduce complex protein syntheses inside cells. The more realistic whole-cell-variable-volume (WCVV) approach is exemplified when developing modular kinetic representations of the homeostatic gene expression regulatory modules (GERM) that control the protein synthesis and homeostasis of metabolic processes. In the first part, the general concepts of the WCVV modelling is presented, while in the second part of the paper, past and current experience with GERM linking rules is presented in order to point-out how optimized globally efficient kinetic models for the genetic regulatory circuits (GRC) can be obtained to reproduce experimental observations. Based on quantitative regulatory indices evaluated vs. simulated dynamic and stationary environmental perturbations, the paper exemplifies with GERM-s from E. coli, at a generic level, how this methodology can be extended: i) to characterize the module efficiency, species connectivity and system stability; ii) to build-up modular regulatory chains of various complexity; iii) to prove feasibility of the cooperative vs. concurrent construction that ensures an efficient gene expression, system homeostasis, proteic functions and a balanced cell growth during the cell cycle; iv) to prove the effect of the whole-cell content ballast in smoothing the effect of internal/external perturbations on the system homeostasis.