Redrawing the Ramachandran plot after inclusion of hydrogen-bonding constraints

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 1; pp. 109 - 113
• Main Authors: Porter, Lauren L, Rose, George D
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04.01.2011; National Acad Sciences
• Series: From the Cover
• Subjects: Amides; Amides - chemistry; Amides - metabolism; Atoms; Biological Sciences; Bridge engineering; Conformity; Databases, Protein; Degrees of freedom; Hydrogen; Hydrogen Bonding; Hydrogen bonds; Inflection points; Models, Molecular; Molecular Dynamics Simulation; Peptides; Protein Conformation; Protein Folding; Proteins; Quadrants; Solvents
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1014674107

A protein backbone has two degrees of conformational freedom per residue, described by its φ,ψ-angles. Accordingly, the energy landscape of a blocked peptide unit can be mapped in two dimensions, as shown by Ramachandran, Sasisekharan, and Ramakrishnan almost half a century ago. With atoms approximated as hard spheres, the eponymous Ramachandran plot demonstrated that steric clashes alone eliminate [fraction three-quarters] of φ,ψ-space, a result that has guided all subsequent work. Here, we show that adding hydrogen-bonding constraints to these steric criteria eliminates another substantial region of φ,ψ-space for a blocked peptide; for conformers within this region, an amide hydrogen is solvent-inaccessible, depriving it of a hydrogen-bonding partner. Yet, this "forbidden" region is well populated in folded proteins, which can provide longer-range intramolecular hydrogen-bond partners for these otherwise unsatisfied polar groups. Consequently, conformational space expands under folding conditions, a paradigm-shifting realization that prompts an experimentally verifiable conjecture about likely folding pathways.