Security groups and role assignments are project-scoped and would work reasonably well in this scenario. And yes, the "look and feel settings" set on a per project basis would help, as far as they go. Beyond that, treating projects as separate "sites" could be an uphill battle. In addition to the home project, there are quite a few site-wide resources, settings, and pages that might need to become project-scoped. Some that come to mind: the Shared project, base server URL, authentication settings, headers/footers/site welcome page, scripting engines, email templates, user management workflows, et al. You'd still be stuck with a single group of site administrators, site settings, and users (maybe that's what you want), and you'd have to be very prescriptive with role assignments to ensure that projects don't bleed into other "sites."

One easier alternative: Take advantage of LabKey's new cloud services, low-cost (or free, depending on your Premium Edition) hosting options that offload all the configuration and maintenance of your deployments. Your multiple sites could be administered and scaled independently. LabKey Cloud Services

Another alternative: Deploy your sites on-premise on a shared machine or VM. Use a single machine, database server, Tomcat instance, and LabKey distribution, but separate databases for each site. Configure Tomcat to respond to multiple domains. This would give you independent sites with distinct URLs but easier maintenance compared to distinct machines for each site.

Adam