Distance‐scaled, finite ideal‐gas reference state improves structure‐derived potentials of mean force for structure selection and stability prediction

TLDR

Existing distance‑dependent structure‑derived potentials use a residue‑averaged reference state. The study introduces the DFIRE distance‑scaled, finite ideal‑gas reference state. Using DFIRE, the authors construct a residue‑specific all‑atom potential of mean force from 1,011 high‑resolution, nonhomologous protein structures and compare it to several physical‑based potentials. The DFIRE all‑atom potential raises average Z‑scores by 1.4 units over two prior residue‑specific potentials, accurately predicts stabilities of 895 mutants, and, when limited to backbone/Cβ atoms, performs comparably to earlier all‑atom potentials.

Abstract

The distance-dependent structure-derived potentials developed so far all employed a reference state that can be characterized as a residue (atom)-averaged state. Here, we establish a new reference state called the distance-scaled, finite ideal-gas reference (DFIRE) state. The reference state is used to construct a residue-specific all-atom potential of mean force from a database of 1011 nonhomologous (less than 30% homology) protein structures with resolution less than 2 A. The new all-atom potential recognizes more native proteins from 32 multiple decoy sets, and raises an average Z-score by 1.4 units more than two previously developed, residue-specific, all-atom knowledge-based potentials. When only backbone and C(beta) atoms are used in scoring, the performance of the DFIRE-based potential, although is worse than that of the all-atom version, is comparable to those of the previously developed potentials on the all-atom level. In addition, the DFIRE-based all-atom potential provides the most accurate prediction of the stabilities of 895 mutants among three knowledge-based all-atom potentials. Comparison with several physical-based potentials is made.