Accumulation of plastic waste is a major environmental problem. Enzymes, particularly esterases, play an important role in the biodegradation of polyesters. These enzymes are usually only active on aliphatic polyesters, but a few have showed catalytic activity for semi-aromatic polyesters. Because of the importance of these processes, an atomic-level characterization of how common polyesters are degraded by esterases is necessary. Hereby, we present a molecular dynamics (MD) and quantum mechanics/molecular mechanics MD study of the hydrolysis of a model of polycaprolactone, one of the most widely used biomaterials, by the thermophilic esterase from the archaeon Archaeoglobus fulgidus. This enzyme is particularly interesting because it can withstand temperatures well above the glass transition of many polyesters. Our insights about the reaction mechanism are important for the design of customized enzymes able to degrade different synthetic polyesters.

Intensive efforts have been made to provide better treatments to cancer patients. Currently, nanoparticle-based drug delivery systems have gained propulsion, as they can overcome the drawbacks of free drugs. However, drug stability inside the nanocapsule must be ensured to prevent burst release. To overcome this, drugs conjugated to amphiphilic copolymers, assembled into nanoparticles, can provide a sustained release if endogenously degraded. Thus, we have designed and assessed the drug release viability of polymer-drug conjugates by the human Carboxylesterase 2, for a targeted drug activation. We performed molecular dynamics simulations applying a quantum mechanics/molecular mechanics potential to study the degradation profiles of 30 designed conjugates, where six were predicted to be hydrolyzed by this enzyme. We further analyzed the enzyme-substrate environment to delve into what structural features may lead to successful hydrolysis. These findings contribute to the development of new medicines ensuring effective cancer treatments with fewer side effects.

Biodegradable polymers, obtained via chemical synthesis, are currently employed in a wide range of biomedical applications. However, enzymatic polymerization is an attractive alternative because it is more sustainable and safer. Many lipases can be employed in ring-opening polymerization (ROP) of biodegradable polymers. Nevertheless, the harsh conditions required in industrial context are not always compatible with their enzymatic activity. In this work, we have studied a thermophilic carboxylesterase and the commonly used Lipase B from Candida antarctica (CaLB) for tailored synthesis of amphiphilic polyesters for biomedical applications. We have conducted Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) MD simulations of the synthesis of Polycaprolactone—Polyethylene Glycol (PCL—PEG) model co-polymers. Our insights about the reaction mechanisms are important for the design of customized enzymes capable to synthesize different polyesters for biomedical applications.

PBIs were synthesized from the reaction of perylene bisanhydrides and primary amines in imidazole as solvent. Maleimide, anthraquinone or ferrocene were bonded to the side chain and the S-trityl group was replaced by imidazole in S-trityl cysteine.

Over the years, our research group developed dehydrodipeptides N-capped with aromatic moieties as protease-resistant efficacious hydrogelators, affording self-assembled hydrogels at low (critical) concentrations. Dehydrotripeptides, with different dipeptide sequences and (D,L) stereochemistry, open a wider chemical space for the development of self-assembled soft nanomaterials. In this work, a small library of N-succinylated dehydrotripeptides containing a C-terminal dehydrophenylalanine (∆Phe) residue and a scrambled dipeptide sequence with phenylalanine (Phe) and homophenylalanine (Hph) (L-Phe-L,D-Hph and L,D-Hph-L-Phe) was synthesized and characterized as a potential hydrogelator. Two pairs of diastereomeric tripeptides were synthesized, both as C-protected methyl esters and as deprotected dicarboxylic acids. Peptides with the sequence Hph-Phe-ΔPhe were obtained as a pair (D,L,Z)/(L,L,Z) of diastereomers. Their scrambled sequence analogues Phe-Hph-ΔPhe were obtained also as a diastereomeric (L,D,Z)/(L,L,Z) pair. The effect of stereochemistry (homo- vs. hetero-chirality) and sequence (Phe-∆Phe vs. Hph-∆Phe motif) on the self-assembly, biocompatibility, gelation and rheological properties of the hydrogels was studied in this work. Accessible, both as C-protected methyl esters and as dicarboxylic acids, N-succinylated dehydrotripeptides are interesting molecular architectures for the development of supramolecular nanomaterials. Interestingly, our results do not comply with the well-documented proposition that heterochiral peptides display much higher self-assembly propensity and gelation ability than their homochiral counterparts. Further studies will be necessary to fully understand the interplay between peptide sequence and homo- and hetero-chirality on peptide self-assembly and on the properties of their supramolecular materials.