Creating novel protein scripts beyond natural alphabets

Kumar, Anil; Ramakrishnan, Vibin

doi:10.1007/s11693-011-9068-5

Cited by 18 publications

(9 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…And yet, one can only imagine the multitude of structures and functions available to proteins if a wider array of non-coded amino acids was exploited. While recent advances in molecular biology have allowed for the controlled incorporation of a myriad of different amino acids within proteins using amber codons or post-translational modification [1–3], the most straightforward method of incorporating alternate amino acids in protein engineering is through solid-phase synthesis [4–9]. The introduction of artificial amino acids greatly expands the versatility of the protein sequence pool.…”

Section: Introductionmentioning

confidence: 99%

Incorporation of second coordination sphere d-amino acids alters Cd(II) geometries in designed thiolate-rich proteins

et al. 2017

View full text Add to dashboard Cite

We use a de Novo protein design strategy to demonstrate that the second coordination sphere of a metal site plays a key role in controlling coordination geometries of Cd(II)-tris-thiolate complexes. Specifically, we show that alteration of chirality within the core hydrophobic packing region of a three-stranded coiled coil (3SCC) can control the coordination number of Cd(II) by limiting steric encumbrance to the metal center. Within a specific class of 3SCCs [Ac-G-(LKALEEK)n-G-NH2], where n = 4 is TRI and n = 5 is GRAND, one l-Leu may be substituted by l-Cys to generate a planar tris-thiolate array capable of metal binding. In the native peptide containing only the l-configuration of leucine, the three-Cys ligand site leads to a mixture of 3- and 4-coordinate Cd(II). When the l-Leu above (toward the N-terminus) the tris-Cys site is substituted with d-Leu, solely a 3-coordinate structure [Cd(II)S3] was obtained. When d-Leu is located below (toward the C-terminus), a mixture of two coordination geometries, presumably Cd(II)S3O and Cd(II)S3O2, is observed, while substitution with d-Leu both above and below the tris-Cys plane yields a higher percentage of 4-coordinate Cd(II)S3O species. Thus, the use of d-amino acids around a metal’s coordination sphere provides a powerful tool for controlling the properties of future designed metalloproteins.

show abstract

Section: Introductionmentioning

confidence: 99%

Incorporation of second coordination sphere d-amino acids alters Cd(II) geometries in designed thiolate-rich proteins

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Hypothetically, if we add one more variable as ‘stereochemistry of amino-acids’ in the backbone, number of stereo-isomeric diversity increases exponentially from 1 n to 2 n . The entire protein universe, nonetheless, is made of only one of them (poly L-chiral or isotactic), which means (2 n − 1) is yet to be explored, and experiments in this direction may have a huge impact in biomaterials research 18 , 19 .…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial effects of syndiotactic polypeptides

Hazam

Phukan

Akhil

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

We present design and antibacterial studies of stereochemically diversified antimicrobial peptides against multidrug-resistant bacterial pathogens. Syndiotactic polypeptides are polymers of alternating L and D amino acids with LDLD or DLDL backbone stereochemical sequence, which can form stable gramicidin like helical conformations. We designed, synthesized and characterized eight model molecular systems with varied electrostatic fingerprints, modulated through calibrated sequence positioning. Six out of eight model systems showed very impressive antimicrobial activity against three difficult to treat bacterial species, Gentamicin resistant MRSA, E. coli and Mycobacterium. More importantly, the designed LDLD peptides were equally potent in serum, an important drawback of poly L peptide sequences due to enzyme mediated degradation and ion sensitivity. Further, we tested the activity of the designed peptides against drug-resistant clinical isolates of Staphylococcus aureus and Escherichia coli. Molecular dynamics simulation studies suggest formation of an assembly of individual peptides, preceding the membrane interaction and deformation. The activity estimates are comparable with the available peptide based antimicrobials, and are also highly specific and less toxic as per standard estimates. Incorporation of D amino-acids can significantly expand the peptide design space, which can in turn manifest in future biomaterial designs, especially antimicrobials.

show abstract

“…Though disordered peptides can also penetrate live cell membranes, the designability of such intrinsically disordered peptides as CPPs is limited . The uncertainty in adopting a specific fold further adds to the obstacles for designing CPPs with tailored functions . To design peptides with tailored functions, it is vital to confine the peptide backbone architecture to a defined conformation; else, we have to wait for random hits with very minimal possibility of an informed and structured design paradigm getting established .…”

Section: Introductionmentioning

confidence: 99%

“…13 The uncertainty in adopting a specific fold further adds to the obstacles for designing CPPs with tailored functions. 14,15 To design peptides with tailored functions, it is vital to confine the peptide backbone architecture to a defined conformation; else, we have to wait for random hits with very minimal possibility of an informed and structured design paradigm getting established. 16 A stable template structure offers the possibility of optimizing design parameters like amphipathicity, topology, overall size, and sequence length.…”

Section: Introductionmentioning

confidence: 99%

Conformationally constrained peptides for drug delivery

Jerath

Goyal

Trivedi

et al. 2020

Journal of Peptide Science

Self Cite

View full text Add to dashboard Cite

Peptides have shown great potential in acting as template for developing versatile carrier platforms in nanomedicine, aimed at selective delivery of drugs to only pathological tissues saving its normal neighbors. Cell‐penetrating peptides (CPPs) are short oligomeric peptides capable of translocating across the cell membrane while simultaneously employing multiple mechanisms of entry. Most CPPs exist as disordered structures in solution and may adopt a helical conformation on interaction with cell membrane, vital to their penetrative capability. Herein, we report a series of cationic helical amphipathic peptides (CHAPs), which are topologically constrained to be helical. The peptides were tested against cervical and breast cancer cells for their cell penetration and drug delivery potential. The cellular uptake of CHAP peptides is independent of temperature and energy availability. The activity of the peptides is biocompatible in bovine serum. CHAPs delivered functional methotrexate (MTX) inside the cell as CHAP‐MTX conjugates. CHAP‐MTX conjugates were more toxic to cancer cells than MTX alone. However, the CHAP‐MTX conjugates were less toxic to HEK‐293 cells compared with the cancer cells suggesting higher affinity towards cancer cells.

show abstract

Creating novel protein scripts beyond natural alphabets

Cited by 18 publications

References 68 publications

Incorporation of second coordination sphere d-amino acids alters Cd(II) geometries in designed thiolate-rich proteins

Incorporation of second coordination sphere d-amino acids alters Cd(II) geometries in designed thiolate-rich proteins

Antimicrobial effects of syndiotactic polypeptides

Conformationally constrained peptides for drug delivery

Contact Info

Product

Resources

About