Denver is indeed located on I-70, which is a major highway and part of the original Eisenhower system. I-70 follows the old route of US-40, which itself followed, in the east, “The National Road,” and in the west, a major wagon route to the mining boom-towns of Colorado. Denver’s growth was largely a feature of the mining industry’s growth, which further goes to show the importance of geographic specificity. A given bit of land was uniquely advantageous to a specific labor-intensive industry, ergo, a city was born. By 1859, Denver had one of the only express overland mail routes in the region, and by 1863 was the recognized regional hub for mail. By 1870, they had a spur to the Transcontinental Railroad in Cheyenne, less than 5 years after the railroad reached there, paid for by locally-raised capital. All that to say: yes, geography had quite a role to play. Even before mining, the banks of the South Platte and Cherry Creek had been long-term camping grounds for major native American populations, because they were a logical meeting of ways in the area.
If pure complementarity effects were the dominant driver of urban formation, we’d see cities out in the middle of the plains. We don’t see many cities dumped out in the plains. We see them at geographic choke points, and their populations respond to innovations in technology, especially construction and transportation technology, as well as shifting local industrial makeup.
Regarding populated places along the Missouri, I give you:
Sioux Falls, Council Bluffs, Kansas City, Jefferson City, Omaha, Bismarck, and Pierre. There’s a swathe of population density along the Missouri river stretching from the Dakotas to St. Louis, where areas along the river are more populated than areas just a few counties out. Because, again, geography matters.
Also, just FYI, the Kansas City metro area has more people than the Austin metro area, so unless you’re using some very odd definitions of the Great Plains, you’d need to include KC.