Selecting near‐native conformations in homology modeling: The role of molecular mechanics and solvation terms

• Published in: Protein science Vol. 7; no. 8; pp. 1772 - 1780
• Main Authors: Janardhan, Ajit, Vajda, Sandor
• Format: Journal Article
• Language: English
• Published: Bristol Cold Spring Harbor Laboratory Press 01.08.1998
• Subjects: Bacterial Proteins; Computer Simulation; Databases, Factual; Eosinophil-Derived Neurotoxin; free energy; loop closure; Models, Chemical; Monomeric GTP-Binding Proteins; NM23 Nucleoside Diphosphate Kinases; Nucleoside-Diphosphate Kinase; Phosphoenolpyruvate Sugar Phosphotransferase System - chemistry; Protein Binding; Protein Conformation; Proteins - chemistry; Receptors, Retinoic Acid - chemistry; Ribonucleases; Sequence Homology, Amino Acid; side‐chain search; Solvents; Thermodynamics; Transcription Factors - chemistry
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.5560070812

A free energy function, combining molecular mechanics energy with empirical solvation and entropic terms, is used for ranking near‐native conformations that occur in the conformational search steps of homology modeling, i.e., side‐chain search and loop closure calculations. Correlations between the free energy and RMS deviation from the X‐ray structure are established. It is shown that generally both molecular mechanics and solvation/entropic terms should be included in the potential. The identification of near‐native backbone conformations is accomplished primarily by the molecular mechanics term that becomes the dominant contribution to the free energy if the backbone is even slightly strained, as frequently occurs in loop closure calculations. Both terms become equally important if a sufficiently accurate backbone conformation is found. Finally, the selection of the best side‐chain positions for a fixed backbone is almost completely governed by the solvation term. The discriminatory power of the combined potential is demonstrated by evaluating the free energies of protein models submitted to the first meeting on Critical Assessment of techniques for protein Structure Prediction (CASP1), and comparing them to the free energies of the native conformations.