Research
Understanding Protein Allostery
We are very interested in understanding the function of biomolecules. Some of the interesting systems that we studied so far were: 1. Dimeric hemoglobin 2. HIV-1 reverse transcriptase 3. Green Fluorescent Protein 4 Photoactive Yellow Protein, etc., The main methodology, we have used is tracking the vibrational energy transport pathways. Two different methodologies have been used. In one method, considering the kinetic energy of the atoms, we start with a quenched structure and introduce an excitation in the form of a wave packet. From the propagation of the wave-packet, we could track the vibrational energy flow in the system. Alternatively, in another method, study the vibrational energy diffusivity using a heat current operator. Both methodology details are provided in the reference below.
Reference:
Ramachandran G., Yao X., Leitner D. M., ”Dynamics of water confined in proteins: A molecular dynamics simulation study of interfacial waters in a dimeric Hemoglobin” J. Phys. Chem. B 2010, 114, 16989-16996.
Ramachandran G., Johnson K. A., Leitner D. M., ”Communication maps computed for homodimeric hemoglobin: Computational study of water mediated energy transport in proteins” J. Chem. Phys. 2011, 135, 065103-10.
Ramachandran G. “Probing the Communication of deoxythymidine triphosphate in HIV-1 Reverse Transcriptase by Communication Maps and Interaction Energy Studies.” Phys. Chem. Chem. Phys. 2017, 19, 29608-29616.
Ramachandran G, Y. Xu "Understanding the Energetic Components Influencing the Thermodynamic Quantities of Carbonic Anhydrase Protein upon Ligand Binding" ChemistrySelect, 2022, 7, e202200024
Water Dynamics
Water plays a vital role in protein allostery. So, it becomes inevitable to study the dynamics of water molecules embedded within the protein environment. The dynamics of water molecules depends upon the hydrophobic and hydrophilic nature of proteins, the availability of space, etc., The dynamics of water molecules in the confined region are of particular interest to us. For example, in the interfacial region of dimeric-HbI, in the GFP protein barrel, and in HIV-1 RT. To better understand protein function, we also investigated the dynamics of hydrated water molecules on the surface of antifreeze protein.
In yet another interesting collaboration with THz spectrocopy work, we studied the dynamics of water molecules in the presence of alkali metal and halogen atoms existing in different concentrations. Here we explained the rattling motions (oscillations) of the anions and cations correlating with THz spectra. Some of the references are listed here:
Yao X., Ramachandran G., Leitner D. M.,”The dielectric response to photoexcitation of GFP: A molecular dynamics study” Chem. Phys. Lett. 2013, 564, 78-82.
Yao X., Ramachandran G., Leitner D. M.,”Analysis of water and hydrogen bond dynamics at the surface of antifreeze protein” J. At. Mol. and Optical Phys. 2012, 2012, Article ID 125071.
Diedrich A. S., Ozgur B., Stefen F., Benjamin P.B., Ramachandran G., Gerard W. S.,Leitner D. M., and Martina H. ”Rattling in the cage: Ions as probes of sub-picosecond water network dynamics”. J. Am. Chem. Soc. 2009, 131, 18512.
In silico Drug Design
Structure-based drug design was carried out for some interesting systems. Notable among them were 1. identifying a suitable drug for the carbonic anhydrase enzyme and 2. bacterial adenylate cyclases.
A. Pecina, J. Brynda, L. Vrzal, G. Ramachandran, M. Horejsi, S. M. Eyrilmez, Jan Rezac Martin Lepsik, Pavlina Rezacova, Pavel Hobza, Pavel Majer, Vaclav Veverka, Jindrich Fanfrlik “Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II-Inhibitor Complexes” ChemPhysChem. 2018, 19, 873-879.
J. Frydrych, J. Skácel, M. Šmídková, H. Mertlíková-Kaiserová, M. Dračínský, Ramachandran G., M. Lepšík, M. Soto-Velasquez, V. J. Watts, Z. Janeba, “Synthesis of α‐branched acyclic nucleoside phosphonates as potential inhibitors of bacterial adenylate cyclases” ChemMedChem. 2018, 13, 199-206.
Non- Covalent Interactions
In drug design, non-covalent interaction is important in identifying a suitable ligand. The contribution of non-covalent interaction energy cannot be neglected. Classical methods, although they identify the structural conformation, do not yield good results for non-covalent interaction energies due to hydrogen/halogen/pnicogen bonding, pi-pi interaction, pi-sigma bond interaction, etc. So, we need to depend on semi-empirical or quantum methods. Some of our interesting publications related to non-covalent interactions are listed here:
Susanta Halder, Ramachandran G., Pavel Hobza “A comparison of ab-initio Quantum- Mechanical and Experimental D0 Binding Energies for Eleven H-Bonded and Eleven Dispersion-Bound Complexes” , Phys. Chem. Chem. Phys., 2015, 17, 26645-26652.
Ashish T.K., Priyanka S., Ved P. S. Praveen. S., Pankaj S., Ramachandran G., Hobza P., “Selective induced polarization through electron transfer in non-polar substrates”, New Journal of Chemistry, 2014, 38, 4885-4892.
Normal Mode Analysis
The stability of a system can be determined by normal mode analysis (NMA). Most of the electronic structure packages use Cartesian coordinates for the vibrational spectra analysis. Transforming the cartesian coordinates to normal coordinates, i.e., in terms of bond length, bond angle, torsion, etc., we get a better picture of potential energy distribution. We carried out NMA on some interesting systems, which are listed below. But one drawback is that, NMA is mostly done within harmonic approximation. So, in the future, we are looking forward to understanding the anharmonic contribution to energy distribution.
Ramachandran G. “Normal Modes and Duschinsky Mixing of Ground and Excited State Vibrations of the Green Fluorescent Protein Chromophore” Chem. Phys. Lett. 2013, 587, 61-67.
Ramachandran G., ”Vibrational Spectra of Cyclooctatetraene alkali metal complexes [C8H8M2 (M= Na,K)]” Vibrational Spectroscopy, 2011, 57, 288-293.
Reaction Mechanism and conformational analysis
It is always interesting to study the reaction mechanism and conformational analysis for simple organic systems. Many collaborations in experimental research become great successes. Some of the references are listed below.
D. Elumalai, G. Ramachandran, S. Leelakrishnan, G. Nachimuthu, T. Kannan, T. P. Paramasivam, K. Jayabal “InCl3 - Assisted Eco-Friendly Approach for N-Fused 1,4-Dihydropyridine Scaffolds via Ring Opening Michael Addition of Cyclic Nitroketene and Iminocoumarin: Synthesis and DFT Studies” ChemistrySelect 2018, 3, 2070-2079.
Hari Krishnan, Ramachandran G., Ramaraj, R. C. “Controlled, Sequential approach to Synthesize Sterogenic Methanes via In-situ Generated Reactive Intermediates” ChemistrySelect 2016, 1, 3022.
Sunil R., Praveen S., Ranjeet K., Ashish T. K., Jiří Hostaš, Ramachandran G., Pavel Hobza “Experimental and Theoretical Study on Assessing the Conformational Stability of Polymethylene Bridged Heteroaromatic Dimers: A Case of Unprecedented Folding” Crystal Growth and Design, 2016, 16, 1176-1180.