The search for low energy conformational families of small peptides: Searching for active conformations of small peptides in the absence of a known receptor

Abstract

Breast cancer is the most common cancer among women. Tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment, yet many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Therefore, scientists are searching for breast cancer drugs that have different molecular targets. Previous work revealed that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat model systems, interacting with an unknown receptor, while peptides smaller than eight amino acids did not inhibit breast cancer. We have shown that the use of replica exchange molecular dynamics predicts structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. These simulations identified smaller peptide analogs with a conserved turn, a ␤-turn formed in the larger peptides. These analogs inhibit estrogen- dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition. We outline the computational methods that were tried and used with the experimental information that led to the successful completion of this research.

Structural Analysis of α-Fetoprotein (AFP)-like Peptides with Anti-Breast-Cancer Properties

“…14, 16 We strongly confirm the evidence for the presence of a β-turn in the AFPeps that was predicted by REMD simulations using the AMBER force field. 14,15 To the extent that the β-turn percentages correlate with inhibition rates, these peptides should have inhibiting properties.…”

Building better fibrin knob mimics: an investigation of synthetic fibrin knob peptide structures in solution and their dynamic binding with fibrinogen/fibrin holes

“…Molecular modeling and molecular dynamics (MD) simulations are an emerging approach that explores the conformational landscape of short peptides enabling one to assess molecular structural differences that influence functional binding parameters. 16,17 In this study, we investigated fibrin knob peptide:hole interactions with both experimental and theoretical modeling approaches to elucidate factors that influence the kinetic binding dynamics (k a and k d ) of knob A peptide variants to fibrin holes. We focused on (1) kinetic modeling of the binding interaction and (2) structural characterization of the peptides in solution.…”

Twenty years of exceptional success: The molecular education and research consortium in undergraduate computational chemistry (MERCURY)

“…The Principal Investigator (PI) invited five additional investigators into the consortium during the grant period: Mauricio Cafiero ( Rhodes College , biochemistry), Kelling Donald ( University of Richmond , chemical bonding), Becky Eggimann ( Wheaton College , IL , solvation), Daqing Gao ( Queensborough Community College of CUNY , physical organic), and Eric Patterson ( Truman State , physical organic). These MERCURY investigators have published 50 papers, [ 47–96 ] which translates to 1.9 publications/faculty/year (seven faculty were in the consortium for 3 years; five were in the consortium for 1 year). This is 3.8 times the national average (0.5 pubs/faculty/year).…”

“…[ 364,365 ] From 2001, when the first NSF‐MRI grant was funded, through the summer of 2019, the MERCURY investigators have published 361 peer‐reviewed publications, including 2 in Chemical Society Reviews , [ 104,269 ] 1 in Chemical Reviews , [ 41 ] 1 in Nature Reviews Chemistry , [ 328 ] 3 in Science , [ 160,184,272 ] 2 in Nature , [ 271,344 ] 2 in Angewandte Chemie International Edition , [ 199,346 ] 13 in JACS , [ 20,24,26,36,59,71,84,112,136,169,289,315,336 ] and 3 in PNAS . [ 5,148,318 ] We published 44 papers during the first MRI grant period, [ 2–45 ] 50 during the second MRI grant period, [ 47–96 ] 62 during the third MRI grant period, [ …”