Even if someone uses an interface for the first time, certain elements can still be familiar.
Page layouts come in many guises, one column, two column, left or right sidebar, centered, liquid and more.Before any content makes it into the bare-bones of a layout, consideration needs to be given to the construction of the design and how the content needs to be presented. Without layout decided, consideration needs to be given to positioning of elements, IE header, footer, sidebar, and columns. This is dictated by the content that needs to appear within the confines of the home page.
Traditionally, headers and footers appear at the top and button of page and there is little reason to change this. And typically sidebar is placed right, less mouse travel of the majority of users.
With the layout web designer needs to think about content, as most users will read from left to right. Also, give content breathing space, make sure that content is not squeezed into small section and text is big enough to read. Try to avoid long pages as visitors will get tired of scrolling.