A protein’s function is inherently linked to its secondary and tertiary structure, which is determined by its amino acid sequence. Understanding the structures of various disease-linked proteins is, therefore, a crucial step towards designing modulators that can influence protein function. When considering the conformational propensity of a polypeptide, given that the CO-NH peptide bond atoms have a very stable planar conformation, it is apparent that the secondary structure -determining coordinates are the two backbone dihedral angles that occur between atoms CO-NH-C(α)-CO (Φ) and NH-C(α)-CO-NH (Ψ). This idea was first introduced by Ramachandran et al. in the 1960s, who hypothesised that only certain regions of Φ / Ψ space are energetically feasible given the minimum contact distances permitted by the van der Waals interactions between atoms in adjacent residues (https://doi.org/10.1016/S0022-2836(63)80023-6). Indeed, when Ramachandran et al. analysed structural data from di-, tri- and poly-peptides, they found that all of the structures resided within the theoretically permitted regions of Φ / Ψ space, and that the space occupied was characteristic of the secondary structure present in the polypeptide chain.
Stereochemistry of polypeptide chain configurations.
Today, Ramachandran analysis remains a staple for protein structure validation and secondary structure analysis/ parameterisation of molecular models and simulations:
Structural biology data archiving – where we are and what lies ahead.
A New Generation of Crystallographic Validation Tools for the Protein Data Bank.
Combining Ramachandran plot and molecular dynamics simulation for structural-based variant classification: Using TP53 variants as model.
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