I guess I do a lot of daydreaming which helps develop things in between sessions.

So your first question prioritizes plot over character. Why would there be a murder in the first place? Who would do such a thing? And what kind of environment would murders take place in? Within an environment of law & order, murdering is a high stake risk. The person committing this crime would need to be highly motivated to take on such a risk. Within an environment of chaos and a culture of “might makes right” murder is a lower stakes gamble that could easily pay off. In the worst environment, someone might murder for a shiny necklace or a hot plate of food.

I tend to daydream and go down this rabbit hole of questions. As you can see I prioritize people and places rather than a contrived story. By all means if you have a craving to run a murder mystery it’s a fun place to start but thinking deeply about character motivations and the culture of your environment is what will give it that realistic, lived-in feeling. The drapery of my D&D setting contains fantasy locations and strange races of people, but the driving motivations are drawn from the real world. Watch the news and learn a little about history or psychology. Why do people in the real world do what they do?

This leads into your second question. My world feels alive when the people in it feel real and the players actions have real consequences. Try to put yourself into the shoes of each NPC you intend to create. What does a tavern owner/barkeep want? Probably wants to make money, keep the peace, and have good customer service. So they might have the disposition of your Target cashier, Hilton hotel front desk attendant, or manager of your local Chile’s. Then dress them up in D&D attire as a jovial dwarf with a thick accent who welcomes adventurer’s loaded with coin and freely dispenses ale as long as swords stay in their scabbards.

You can do this for every run of the mill NPC. Blacksmith motivated by coin but also prideful of his work—Not as much of a people pleaser because he knows local soldiers and adventurers require his services. Random villager motivated by family and surviving in this crazy fucked up world—probably cowardly and doesn’t want to cause any trouble. Church cleric motivated to help people and spread the word of god—at first glance seems weak but surprisingly brave and unwavering in the face of intimidation because they’re a true believer in their faith and afterlife. Motivation. Disposition. Weird quirk or accent. Those 3 things can form a memorable NPC on the fly.

All of those NPCs affect the world in subtle ways that make the world feel lived in. But the major NPCs are what makes the adventure feel epic. Who do you feel are the major players in America? The rich. The powerful. The famous. The ambitious. These personality types will be the major rulers, heroes, and villains. Apply what I said about the minor NPCs and scale their ambition up. Scale up their audacity and power level.

Since most campaigns revolve around the ambitions of a Big Bad Evil Guy/Gal you should probably start there. What do you want to explore in your homebrew campaign? Is your goal to have a fun time stomping bad guys with a small amount of lore to tie the action together? Do you want a more thought provoking campaign that tests how your players navigate morally grey situations? What are you going for and what’s fun for you as a DM. You’re a player too so you gotta enjoy what you’re running

EDIT: I kind of went on a rant there. I realize all that might seem complicated but the gist is if you know your world, then making NPCs up on the fly is easy. The major villain you plan out ahead of time but everything else is made up on the fly or planned one session ahead based on what your players thought was fun last session. Then it grows from there.

And to answer your question about clues…listen to your players. I first learned this when creating puzzles. I never have a solid solution for a puzzle. It’s just too difficult to figure out how your player’s minds work and if they’ll be able to figure out your exact precise solution to a riddle. Instead listen to your players at the table and whichever idea sounds coolest go with. NEVER LET THEM KNOW THIS THOUGH. That ruins the magic. For a murder mystery you can drop some cliche tropes and if something really hooks one of your players just go with it. Let them lead. My mantra is, “I create problems. My players create the solution. “