Molecular dynamics investigations on the effect of D amino acid substitution in a triple-helix structure and the stability of collagen.

Studies on the structure and stability of peptides and proteins during l-->d configurational change are certainly important for the designing of peptides with new biological activity and protein engineering. The l-->d amino acid (d AA) changes have been observed in aged proteins such as collagen. Hence, in this study, an attempt has been made to explore the effect of the replacement of l amino acid (l AA) in the model collagen-like peptides with d AA and the origin of structural stability (destability) has been traced using the molecular dynamics (MD) method employing the AMBER force field. Our results reveal that the substitution of d AA produces a large local disruption to the triple-helical structure. Formation of a kink (bulge) at the site of substitution is observed from the detailed analysis of MD trajectory. However, this local perturbation of kinked helix changes the direction of the helices and affects the relative orientation of the respective AA residues for helix-helix interaction, enough to affect the overall stability of the model collagen-like peptide. The destabilization energy per d Ala substitution is 7.87 kcal/mol, which is similar to the value for the Gly-->Ala mutation in collagen. Since the Gly-->Ala mutation is involved in genetic disorders such as osteogenesis imperfecta (OI), the l-->d configurational change may produce a similar effect on collagen.

Helix forming tendency of valine substituted poly-alanine: a molecular dynamics investigation.

In this study, classical molecular dynamics simulations have been carried out on the valine (guest) substituted poly alanine (host) using the host-guest peptide approach to understand the role of valine in the formation and stabilization of helix. Valine has been substituted in the host peptide starting from N terminal to C terminal. Various structural parameters have been obtained from the molecular dynamics simulation to understand the tolerance of helical motif to valine. Depending on the position of valine in the host peptide, it stabilizes (or destabilizes) the formation of the helical structure. The substitution of valine in the poly alanine at some positions has no effect on the helix formation (deformation). It is interesting to observe the coexistence of 3 10 and alpha-helix in the peptides due to the dynamical nature of the hydrogen bonding interaction and sterical interactions.

Role of length-dependent stability of collagen-like peptides.

Understanding the structure, folding, and stability of collagen is complex because of its length and variations in the amino acid (AA) sequence composition. It is well known that the basic constituent of the collagen helix is the triplet repeating sequence of the form Gly-X(AA)-Y(AA). On the basis of previous models and with the frequency of occurrence of the triplets, the ((Gly-Pro-Hyp)n)3 (where n is the number of triplets) sequence replicate has been chosen as the model for the most stable form of the collagen-like sequence. With a view to understand the role of sequence length (or the number of triplets) on the stability of collagen, molecular dynamics simulations have been carried out by varying the number of triplet units on the model collagen-like peptides. The results reveal that five triplets are required to form the stable triple helix. Further analysis shows that the intermolecular structural rigidity of the imino acid residues, hydrogen bonding, and water structure around the three chains of the triple helix play the dominant roles on its structure, folding, and stabilization.

Role of aspartic acid in collagen structure and stability: A molecular dynamics investigation.

A molecular dynamics (MD) simulation study has been carried out to understand the stability of the triple helical collagen models. The calculations show that the presence of the aspartic acid residue in different positions leads to the local variation in the structure. Analyses of root-mean-square deviation (RMSD), radial distribution function (RDF), puckering effect, dihedral angle variation, hydrogen bond (H-bond), and conformational changes during molecular dynamics simulation reveal that the local perturbation in the sequences, increase in chain flexibility due to removal of five membered rings in the collagen by aspartic acid, change of intermolecular H-bonding pattern, and differences in the association of water are mainly influencing the nature of stabilization of collagen by aspartic acid.

Structure-based virtual screening of novel, high-affinity BRD4 inhibitors.

Bromodomains (BRDs) are a diverse family of evolutionarily conserved protein-interaction modules. Among various members of the bromodomain and extra terminal domain family, BRD4 is found to be an important target for many diseases such as cancer, acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, etc. Therefore, in this study an attempt has been made to screen compounds from NCI Diversity, Drug Bank and Toslab Databases targeting the Kac binding site of BRD4 using molecular docking, molecular dynamics simulations, MM-PB/GBSA binding free energy calculations and steered molecular dynamics simulations. Using virtual screening and docking, we have identified 11 inhibitors. These new inhibitors exhibit binding energy values higher than that of the (+)JQ1 inhibitor which is effective against BRD4. However, due to the toxicity of (+)JQ1, the designing of new inhibitors becomes significantly important. Thus, these new 11 ligands were systematically analyzed using other computational investigations. Results reveal that the compounds ZINC01411240, ZINC19632618 and ZINC04818522 could be potential drug candidates for targeting BRD4. It can also be seen from the results that there is a linear relationship between the results obtained from the SMD simulation and free energy obtained from the MM-PBSA/GBSA approach. This study clearly illustrates that the steered molecular dynamics can be effectively used for the design of new inhibitors.

Structural basis for the varying propensities of different amino acids to adopt the collagen conformation.

Although previous experimental studies have shown the positional preference of different amino acids (AAs) to form a stable triple helical collagen motif, the structural basis for the variations in the sequence and the positional propensity has not been systematically investigated. Thus, we have here probed the origin of the structural stability offered by the 20 naturally occurring AAs to collagen by means of classical molecular dynamics (MD) simulation. Simulations were carried out on 39 collagen-like peptides employing a host-guest approach. The results show that the propensity of the different AAs to adopt collagen-like conformations depends primarily on their ϕ and ψ angle preferences. Changes in these angles upon substitution of different AAs in the X(AA) and Y(AA) positions in the canonical ((Gly-X(AA)-Y(AA))(7))(3) motif dictate the formation of interchain hydrogen bonds, solvent interactions, and puckering of neighboring imino acids and, thus, the structural stability of the collagen. The role of solvent-mediated hydrogen bonds in the stabilization of collagen has also been elucidated from the MD simulations. In addition to the conventional hydrogen bonds known to be present in collagen, a hitherto unidentified direct interchain hydrogen bond, between the X(AA) N-H group and the Hyp O-H group of the neighboring chain, was observed during the simulations. Its occupancy was ∼36% when Leu was present at the X(AA) position.

Exploring the changes in the structure of α-helical peptides adsorbed onto a single walled carbon nanotube using classical molecular dynamics simulation.

Classical molecular dynamics (MD) simulation has been carried out in an explicit solvent environment to understand the interaction between the single walled carbon nanotube (SWCNT) and α-helix. A polyalanine peptide consisting of 40 alanine residues has been chosen as the model for the α-helix (PA(40)). Results reveal that the SWCNT induces conformational changes in PA(40). Furthermore, breakage of hydrogen bonds in the chosen model peptides has been observed, which leads to conformational transitions (α → turns) in different parts of the PA(40). Owing to these transitions, regions of different structural and energetic stability are generated in PA(40) which enable the PA(40) to curl around the surface of the SWCNT. The overall observations obtained from the MD simulations are not significantly influenced by the starting geometry and the choice of the force field. Although the qualities of structural information obtained from the MD simulation using ff03 and OPLS are different, the overall observation derived from the ff03 is similar to that of OPLS. Results from the MD simulation on the interaction of the α-helical fragment of the SNARES protein with the SWCNT elicit that the amino acid composition influences the interaction pattern. The wrapping of the α-helical fragment of the SNARES onto the SWCNT is similar to that of PA(40). Overall, there is a considerable decrease in the helical content of peptides upon interaction with SWCNTs, in agreement with the experimental findings.

Bader's electron density analysis of hydrogen bonding in secondary structural elements of protein.

The hydrogen-bonding (H-bonding) interactions in alpha-helical and beta-sheet model peptides have been studied by using the atoms-in-molecule (AIM) approach. The relative importance of NH...O and CH...O H-bonding interactions in the different secondary elements such as alpha-helix, parallel, and antiparallel beta-sheets have been assessed. The electron density values at the NH...O bond are higher than those of the CH...O bonds in the alpha-helical conformation. The electron density values at the H-bonded critical points (HBCPs) corresponding to NH...O and CH...O interactions are nearly equal in the parallel beta-sheet of the order of 10(-3) au, whereas in the case of antiparallel beta-sheets, rho(rc) values for NH...O and CH...O interactions are of the order of 10(-2) and 10(-3) au, respectively. It is interesting to point out here that the weakening of NH...O interactions in the parallel beta-sheet arrangement is evident from the AIM analysis. This is concomitant with the increase in the NH...O distance in the parallel beta-sheet conformation. In addition to the clear description of H-bonding by electron density at the HBCP, possible good linear relationships between the electron density at ring critical points (RCP) and stabilization energy (SE) have been observed corresponding to the various beta-sheet conformations.