Research

Protein sequencing using solid-state nanopores

Protein sequencing using nanopores indeed holds great promise as an efficient, cost-effective and enzyme-less method. Unlike traditional techniques like Sanger's method and Edman degradation method, which are time-consuming, expensive and enzyme-dependent, nanopore sequencing offers the potential for rapid and high-throughput protein analysis. However, there are several challenges associated with protein sequencing using nanopores due to the complex nature of proteins. To this end, all-atom molecular dynamics simulations have been employed to assess the feasibility of using nanopores for protein detection. Similar to nucleic acids (DNA and RNA), the simulations suggest that it might be possible to achieve uni-directional and stepwise translocation of peptides through nanopores which is crucial for their detection and sequencing in a controlled manner, one amino acid at a time.

Designing oxygen resistance [FeFe]-hydrogenase

The increasing interest in the use of hydrogen as a "clean" alternative to fossil fuels, promotes the use of [FeFe]-hydrogenases as efficient biocatalysts for hydrogen production. This chemical reaction occurs at the active site H-cluster of [FeFe]-hydrogenases comprised of an unique [2Fe2S]-subcluster and a cubane [4Fe4S] cluster, which enables intermittent storage and rapid supply of electrons for the reversible reduction of protons to hydrogen. Unfortunately, this promising biocatalyst is highly sensitive to oxygen, which poses an immense challenge in terms of stabilizing the enzyme under aerobic conditions. Hence, elucidating the molecular determinants of oxygen-sensitivity in [FeFe]-hydrogenases is crucial and represents an essential basis for the development of oxygen-insensitive [FeFe]-hydrogenase.

ACS Catal., 2023, 13, 856-865 DOI:10.1021/acscatal.2c04031
ChemSusChem., 2023, e202301365 DOI:10.1002/cssc.202301365

Solving antibiotic resistance

Escalating antibiotic resistance due to beta-lactamase is a matter of great concern. Therefore, the development of new antibiotics and inhibitors to combat this menace is urgently needed. Efforts are ongoing to obtain the atomistic details of the hydrolysis mechanism in order to develop novel antibiotics and inhibitors against beta-lactamase. We employ extensive hybrid QM/MM enhanced sampling MD simulations and explore the mechanism of acylation and various routes of hydrolysis thereby gaining molecular level insights into beta-lactamase mediated antibiotic hydrolysis mechanism. The mechanistic understanding elicited from computations hold great promises for the future development of antibiotics and inhibitors.

Phys. Chem. Chem. Phys., 2017, 19, 13111-13121 DOI: 10.1039/C6CP08769H
Phys. Chem. Chem. Phys., 2018, 20, 14482-14490 DOI:10.1039/C8CP01670D
Chem. Eur. J., 2020, 26, 9639 DOI:10.1002/chem.202001261
ACS Catal., 2022, 12, 10338-10352 DOI:10.1021/acscatal.2c02693

Dynamics of protein-water network

The dynamics of water molecules buried in protein active site often govern structure and dynamics of the protein. Our all-atom MD simulations visualize how the active site pocket is shaped by open/close conformational‐exchange dynamics of the active site loop and associated active site water molecules. We also compute the absolute entropy of the individual water molecules confined in the active site.

J. Am. Chem. Soc., 2019, 141 (49), 19276-19288 DOI:10.1021/jacs.9b05311
Angew. Chem. Int. Ed., 2020, 59, 22916–22921 DOI:10.1002/anie.202009348
J. Chem. Theory Comput., 2021, 17 (8), 5409-5418 DOI:10.1021/acs.jctc.1c00554

Molecular mechanism of DNA polymerization

Nucleic acid polymerization catalyzed by nucleic acid polymerase lies at the core of genetic inheritance. Often nucleic acid polymerases are considered as effective drug target for the treatment of cancer. In the anti–cancer therapeutic research, telomerase has particularly gained interest because of their hyperactivity found only in the cancer cell. However, the molecular mechanism of DNA polymerization by telomerase remains unclear. We perform QM/MM simulations by which we explore the mechanism at atomic level.

Phys. Chem. Chem. Phys., 2023, 25, 14147-14157 DOI: 10.1039/D3CP00521F

Epigenetic CpG recognition

5-methylcytosine and its TET-oxidized derivatives exist in CpG dyads of mammalian DNA and determine cell fate, but how their individual combinations in the two strands of a CpG act as distinct regulatory signals is not fully understood. Readers that selectively recognize such oxidized CpG duplex mark have great interest in molecular biology. By MD simulations, we unravel crucial molecular features of reader required for recognizing oxidized CpG duplex mark.

Nucleic Acids Res., 2023 DOI:10.1093/nar/gkad134

Molecular machine in a nanocontainer

The dynamics of biomolecular machines that are modulated by various chemical or physical signal activators, can be mimicked by embedding and confining artificial molecular machines within a nanocage in which their functions can be specifically controlled by external stimuli. One such approach is the construction of a supramolecular rotor embedded inside a Zn-bound porphyrin-based cage by encapsulation of a tetrazine-based linear axle through metal-ligand coordination bonds. The addition of pyridine derivatives as a Zn-coordinating ligand induces the rotary movement of the linear axle inside the nanocage. All-atom MD is used to reveal rotary motion of the rotor.

Chem., 2022, 8 (2), 543-556 DOI:10.1016/j.chempr.2021.12.008

Molecular transport through a synthetic channel

The application of such porphyrin cages is further extended towards synthetic channels for the translocation of molecules across biological membranes. Our computer simulations show that glucose molecules can selectively pass through the nanocage in much higher rates than sterically more bulky sucrose molecules. Interestingly, this glucose transportation rate is found to be controllable by changing the length of alkyl chains attached to the windows of the nanocage.

Angew. Chem. Int. Ed., 2023, 135, e202214236 DOI:10.1002/ange.202214326