প্রোটিন মঙ্গল কাব্য ও অন্যান্য ... : Native deviations from ideality : Essential for protein structural integrity

Probing the role of native deviations in maintaining protein structural integrity

Native deviations in main-chain geometrical parameters seems crucial for structural integrity of proteins. These deviations are non-random, strategic and context dependent and it seems extremely difficult to predict them given the native main- and side-chain torsion angle profiles of a given structure. In this work, proteins of diverse folds and lengths were gathered spanning the four major protein classes and ranging from ~50 to ~375 residues in chain length and the structures rebuilt by (successive forth atom fixations) reverting all main-chain bond lengths, angles and ω-torsions to their corresponding unimodal ideal values (as tabulated in relevant repositories), while retaining native values for all other dihedral angles (φ, ψ, χ). To much of our surprise, this led to such large-scale distortions in the idealized structures (with respect to the original native model) that often their (C^α) RMSDs exceeded 10 Å (Fig. 1). Although the degree of structural distortions is estimated by the RMSDs, its effect on packing and electrostatics can be conveniently assessed using the CP measures [1, 2]. The distortions were more pronounced for larger polypeptide chains (~100 residues or more in length) due to the accumulation of a higher number of angular idealizations. Also, proteins containing greater β-sheet content had more severe deformations most probably rationalized by the distribution in N-C^α-C (τ) angle with respect to secondary structure. Little or no improvement was observed in the quality of the rebuilt structures by either retaining native ω values or utilizing ideal values (for bond angles) derived from a conformation dependent library (CDL) (Fig. 2) (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810841/). Energy minimization of these idealized structures did not improve the (C^α) RMSDs (calculated at a one-to-one atomic correspondence subsequent to superposition) between native and idealized coordinates, which in some instances could not even be superposed onto each other (Table 1). Thus, in summary, in no case could the original structure be reconstituted by any form of energy minimization of the idealized coordinates. Calculations using both unimodal and CDL ideal values were repeated on a larger dataset of ultrahigh resolution (≤ 1 Ǻ) structures, which gave a similar pattern of results. Attempts are being carried out to device strategies to predict these deviations in a structure jammed with its native torsion angles.

Fig. 1. Distortions in the native fold due to the reversal of all main-chain bond lengths, angles and ω-torsions to their corresponding (unimodal) ideal values. (A) the native structure of cyclophilin from L. donovani (2HAQ) and (B) its corresponding idealized structure (C^α-RMSD: 12.86 Ǻ, calculated at one-to-one atomic correspondence).

Fig. 2. Effect of CDL-idealization probed by CP. Distribution for (A) the native polypeptide chain (1PGS) and (B) its corresponding idealized structure generated utilizing CDL ideal values.

Table 1. Structural distortions due to idealization as reflected in the RMSDs.

PDB ID	RMSD (Ǻ) ^a
PDB ID	Idealized vs. native	Idealized & Energy Minimized vs. native ^b
1AKO	13.98	-^c
1BGF	7.30	6.77
1CEM	16.61	17.35
1CHD	22.42	22.18
1CKA	3.05	3.10
1ERZ	24.44	22.78
1HBQ	22.60	-
1IFC	11.30	11.48
1LMB	4.56	4.56
1MKB	-	-
1MLA	23.33	22.05
1PDO	4.56	5.29
1PGS	-	-
1SFP	-	-
1SRV	13.82	-
1STN	18.02	18.10
1UBI	4.31	4.14
2CPL	12.52	12.58
2END	7.64	7.41
2LIS	9.09	9.11

^aRMSDs calculated between C^α atoms of idealized (all main-chain bond lengths, bond angles and ω) and the native coordinates (calculated at a one-to-one atomic correspondence) subsequent to superposition by Dali server.

^bThe same calculation was repeated for energy minimized coordinates subsequent to idealization.

^c‘-’ stands for non-superposable structures.

References:

1. Self-Complementarity within Proteins: Bridging the Gap between Binding and Folding

Sankar Basu, Dhananjay Bhattacharyya, and Rahul Banerjee*

Biophysical Journal, 2012, 102 (11) : 2605-2614