Protein structure-function is a key concept in biochemistry. We used the perspective of domain-specific problem-solving to investigate students' solutions to a well-defined protein structure-function problem. We conducted think-aloud interviews with 13 undergraduate students and performed qualitative content analysis to examine the differences in the domain-general and domain-specific knowledge among correct and incorrect solutions. Our work revealed that students used domain-general and domain-specific knowledge in their problem solving. We also identified difficulties for students with the amino acid backbone, amino acid categorization, and causal mechanisms of noncovalent interactions. Using the identified difficulties, we make recommendations for the design of instructional materials targeted to improve protein structure-function problem solving in the biochemistry classroom.