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EnergyPlus assumes a mixed air model and doesn't model natural ventilation by default. If you want to add the influence of natural ventilation, you will need to use the ZoneVentilation:WindandStackOpenArea object, which is implemented in the Add Wind and Stack Open Area OpenStudio measure (see this post for some notes on it), or you can use the more detailed AirFlowNetwork to include the HVAC system.

Even the airflow network object is limited in what you can do, so you need to determine whether an approximation using EnergyPlus will suffice vs. a full airflow modeling software. The answer to your question largely depends on how you control the HVAC. Questions to ask:

• What is the pressurization control strategy for your HVAC system?
• Do you have zonal HVAC or an air-based system?
• Will your HVAC system run concurrently with open windows?
• This system is operating partly by stack effect, which means you will have non-homogenous air temperature and air speeds in the room. Are you trying to capture air speed and temperature at a specific point, or use a zonal average?