A complete macromolecule modeling package must be able to solve the simplest
structure prediction problems. Despite recent successes in high resolution
structure modeling and design, the Rosetta software suite fares poorly on
deceptively small protein and RNA puzzles, some as small as four residues. To
illustrate these problems, this manuscript presents extensive Rosetta results
for four well-defined test cases: the 20-residue mini-protein Trp cage, an even
smaller disulfide-stabilized conotoxin, the reactive loop of a serine protease
inhibitor, and a UUCG RNA tetraloop. In contrast to previous Rosetta studies,
several lines of evidence indicate that conformational sampling is not the
major bottleneck in modeling these small systems. Instead, approximations and
omissions in the Rosetta all-atom energy function currently preclude
discriminating experimentally observed conformations from de novo models at
atomic resolution. These molecular "puzzles" should serve as useful model
systems for developers wishing to make foundational improvements to this
powerful modeling suite.

通过测试 20 个氨基酸小蛋白的三维结构、小型缩二巯基 - 稳定的海螺毒素、丝氨酸蛋白酶抑制剂的反应环以及 UUCG RNA 四元环等四个建模案例，本文表明 Rosetta 分子建模套件在预测这类小分子方面表现不佳，结论是 Rosetta 强大的取样能力与其全原子能量函数目前还不能区分实验观察到的构象和基于自然演化的全原子复合物.