I am a theoretical and computational biophysicist working at the interface of biology, chemistry, and biophysics. My research primarily focuses on biomolecular interactions, dynamics, structure, and thermodynamics. My systems of interest mainly include proteins, nucleic acids, and lipids. Additionally, I am also interested in machine learning and generative artificial intelligence (AI) for computer-aided drug discovery. Molecular dynamics simulations and statistical mechanics form the backbone of my research.
RESEARCH, TEACHING, or OTHER INTERESTS
Biophysics, Physical and Theoretical Chemistry
32
Scopus Publications
859
Scholar Citations
15
Scholar h-index
20
Scholar i10-index
Scopus Publications
Unlocking the Conformational Secrets of DYRK1A Kinase With Computational Microscope: Exploring Phosphorylation-Driven Structural Dynamics Kapil Dattatray Ursal, Md Fulbabu Sk, Subhasmita Mahapatra, Parimal Kar Journal of Computational Chemistry, 2025 The intricate world of cellular processes relies significantly on the dual‐specificity tyrosine‐phosphorylation‐regulated kinase (DYRK) family of kinases, governing vital functions like brain development, splicing regulation, and apoptosis. DYRK1A, in particular, stands at the center of attention due to its pivotal role. Disruptions in its activity, whether through upregulation or downregulation, have profound implications, notably in neurological disorders and cancer progression. Understanding the impact of phosphorylation, a fundamental post‐translational modification, on DYRK1A is paramount. In this study, we delved into the complex interplay of phosphorylation and the effects of the abemaciclib inhibitor on DYRK1A conformational dynamics. We employed advanced techniques such as molecular dynamics simulations and the molecular mechanics Poisson‐Boltzmann surface area (MM/PBSA) scheme and deciphered the intricate dance of DYRK1A's structural elements during phosphorylation. Our exploration revealed intriguing details: the αC‐helix undergoing outward movement, a distorted αC‐helix, a wide‐open P‐loop, extended A‐loop, and role of electrostatic interactions shaping A‐loop dynamics. Notably, the interaction of specific residues, particularly Lys188, forming robust salt bridges with Asp307 and Glu203, plays a pivotal role in shaping the structure of the protein. Diving deeper, we conducted principal component analysis and conformational free energy sampling to uncover crucial structural intermediates. Moreover, our dynamic cross‐correlation map sheds light on the influence of phosphorylation by enhancing coordinated movements while dampening anti‐correlated motions across various domains. This nuanced understanding of DYRK1A kinase activation, driven by phosphorylation, not only enriches our knowledge but also holds promise in the development of targeted therapies for associated diseases.
Dynamic Interplay of Loop Motions Governs the Molecular Level Regulatory Dynamics in Spleen Tyrosine Kinase: Insights from Molecular Dynamics Simulations Sunanda Samanta, Md Fulbabu Sk, Suman Koirala, Parimal Kar Journal of Physical Chemistry B, 2024 The spleen tyrosine kinase (Syk) is a key regulator in immune cell signaling and is linked to various mechanisms in cancer and neurodegenerative diseases. Although most computational research on Syk focuses on novel drug design, the molecular-level regulatory dynamics remain unexplored. In this study, we utilized 5 × 1 μs all-atom molecular dynamics simulations of the Syk kinase domain, examining it in combinations of activation segment phosphorylated/unphosphorylated (at Tyr525, Tyr526) and the "DFG"-Asp protonated/deprotonated (at Asp512) states to investigate conformational variations and regulatory dynamics of various loops and motifs within the kinase domain. Our findings revealed that the formation and disruption of several electrostatic interactions among residues within and near the activation segment likely influenced its dynamics. The protein structure network analysis indicated that the N-terminal and C-terminal anchors were stabilized by connections with the nearby stable helical regions. The P-loop showed conformational variation characterized by movements toward and away from the conserved "HRD"-motif. Additionally, there was a significant correlation between the movement of the β3-αC loop and the P-loop, which controls the dimensions of the adenine-binding cavity of the C-spine region. Overall, understanding these significant motions of the Syk kinase domain enhances our knowledge of its functional regulatory mechanism and can guide future research.
Structure of the human dopamine transporter and mechanisms of inhibition Dushyant Kumar Srivastava, Vikas Navratna, Dilip K. Tosh, Audrey Chinn, Md Fulbabu Sk, Emad Tajkhorshid, Kenneth A. Jacobson, Eric Gouaux Nature, 2024 The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement1. Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, the human dopamine transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn2+ are without a high-resolution structural context. Here we determine the structure of hDAT in a tripartite complex with the competitive inhibitor and cocaine analogue, (–)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane2 (β-CFT), the non-competitive inhibitor MRS72923 and Zn2+ (ref. 4). We show how β-CFT occupies the central site, approximately halfway across the membrane, stabilizing the transporter in an outward-open conformation. MRS7292 binds to a structurally uncharacterized allosteric site, adjacent to the extracellular vestibule, sequestered underneath the extracellular loop 4 (EL4) and adjacent to transmembrane helix 1b (TM1b), acting as a wedge, precluding movement of TM1b and closure of the extracellular gate. A Zn2+ ion further stabilizes the outward-facing conformation by coupling EL4 to EL2, TM7 and TM8, thus providing specific insights into how Zn2+ restrains the movement of EL4 relative to EL2 and inhibits transport activity.
Microsecond dynamics of H10N7 influenza neuraminidase reveals the plasticity of loop regions and drug resistance due to the R292K mutation Md Fulbabu Sk, Sunanda Samanta, Sayan Poddar, Parimal Kar Journal of Computational Chemistry, 2024 At the beginning of the last century, multiple pandemics caused by influenza (flu) viruses severely impacted public health. Despite the development of vaccinations and antiviral medications to prevent and control impending flu outbreaks, unforeseen novel strains and continuously evolving old strains continue to represent a serious threat to human life. Therefore, the recently identified H10N7, for which not much data is available for rational structure‐based drug design, needs to be further explored. Here, we investigated the structural dynamics of neuraminidase N7 upon binding of inhibitors, and the drug resistance mechanisms against the oseltamivir (OTV) and laninamivir (LNV) antivirals due to the crucial R292K mutation on the N7 using the computational microscope, molecular dynamics (MD) simulations. In this study, each system underwent long 2 × 1 μs MD simulations to answer the conformational changes and drug resistance mechanisms. These long time‐scale dynamics simulations and free energy landscapes demonstrated that the mutant systems showed a high degree of conformational variation compared to their wildtype (WT) counterparts, and the LNV‐bound mutant exhibited an extended 150‐loop conformation. Further, the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculation and MM/GBSA free energy decomposition were used to characterize the binding of OTV and LNV with WT, and R292K mutated N7, revealing the R292K mutation as drug‐resistant, facilitated by a decline in binding interaction and a reduction in the dehydration penalty. Due to the broader binding pocket cavity of the smaller K292 mutant residue relative to the wildtype, the drug carboxylate to K292 hydrogen bonding was lost, and the area surrounding the K292 residue was more accessible to water molecules. This implies that drug resistance could be reduced by strengthening the hydrogen bond contacts between N7 inhibitors and altered N7, creating inhibitors that can form a hydrogen bond to the mutant K292, or preserving the closed cavity conformations.
Conformational preferences of triantennary and tetraantennary hybrid N-glycans in aqueous solution: Insights from 20 μs long atomistic molecular dynamic simulations Rajarshi Roy, Sayan Poddar, Md Fulbabu Sk, Parimal Kar Journal of Biomolecular Structure and Dynamics, 2023 In the current study, we have investigated the conformational dynamics of a triantennary (N-glycan1) and tetraantennary (N-glycan2) hybrid N-glycans found on the surface of the HIV glycoprotein using 20 μs long all-atom molecular dynamics (MD) simulations. The main objective of the present study is to elucidate the influence of adding a complex branch on the overall glycan structural dynamics. Our investigation suggests that the average RMSD value increases when a complex branch is added to N-glycan1. However, the RMSD distribution is relatively wider in the case of N-glycan1 compared to N-glycan2, which indicates that multiple complex branches restrict the conformational variability of glycans. A similar observation is obtained from the principal component analysis of both glycans. All the puckering states (4C1 to 1C4) of each monosaccharide except mannose are sampled in our simulations, although the 4C1 chair form is energetically more favorable than 1C4. In N-glycan1, the 1–6 linkage in the mannose branch [Man(9)-α(1-6)-Man(5)] stays in the gauche-gauche cluster, whereas it moves towards trans-gauche in N-glycan2. For both glycans, mannose branches are more flexible than the complex branches, and adding a complex branch does not influence the dynamics of the mannose branches. We have noticed that the end-to-end distance of the complex branch shortens by ∼ 10 Å in the presence of another complex branch. This suggests that in the presence of an additional complex branch, the other complex branch adopts a close folded structure. All these conformational changes involve the selective formation of inter-residue and water-mediated hydrogen-bond networks. Communicated by Ramaswamy H. Sarma Graphical Abstract
Exploring molecular interactions of potential inhibitors against the spleen tyrosine kinase implicated in autoimmune disorders via virtual screening and molecular dynamics simulations S. Samanta, M.F. Sk, S. Koirala, P. Kar SAR and QSAR in Environmental Research, 2023 The spleen tyrosine kinase (Syk) plays a pivotal role in immune cells’ signal transduction mechanism. While fostamatinib, an FDA-approved Syk inhibitor, is currently used to treat immune thrombocytopenia, the search for improved Syk-targeted medications to treat autoimmune diseases is still underway. Herein, we screened 38,493 compounds against Syk and selected eight leads based on the docking score and ADMET properties, and performed 3×200 ns long molecular dynamics simulations of the apo and Syk-ligand complexes. We considered R406, the active component of fostamatinib, as a control. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations demonstrated the lead1 (ΔGbind = -30.35 kcal/mol) exhibited a similar binding free energy as the control (ΔGbind= −29.82 kcal/mol). The Syk stabilizing effect of lead1 was also indicated in its network features, sampling space, and residual correlation motion analysis. We further generated 100 structural analogues of lead1 using deep learning, and one of the analogues displayed a better binding free energy (ΔGbind= −47.58 kcal/mol) compared to the control or lead1, facilitated by more favourable van der Waals interactions and lesser binding-opposing net polar forces. This analogue may be further exploited to develop effective therapeutics against Syk-associated diseases after validation in vitro and in vivo.
BPS2026–Designing novel kinase inhibitors with generative AI P Kelich, H Park, MF Sk, Y Li, E Tajkhorshid Biophysical Journal 125 (4), 234a , 2026 2026
BPS2026–Molecular insight into channel stoichiometry and PIP2 binding of Kv7. 2/Kv7. 3 channels with CaM-Ca2+ MF Sk, C Duckworth, AA Kermani, HJ Chung, E Tajkhorshid Biophysical Journal 125 (4), 79a-80a , 2026 2026
Unlocking the conformational secrets of DYRK1A kinase with computational microscope: exploring phosphorylation‐driven structural dynamics KD Ursal, MF Sk, S Mahapatra, P Kar Journal of Computational Chemistry 46 (17), e70172 , 2025 2025 Citations: 1
Small molecules, big impact: A multiscale modeling on protein kinase inhibitors for enhanced therapeutic development MF Sk, T Tyrikos-Ergas, M Burke, E Tajkhorshid ACS Spring 2025, San Diego, USA. 4177957 , 2025 2025
BPS2025-How does MRS7292 stabilize the outward-facing state of the human dopamine transporter? Insights from computational biophysics MF Sk, DK Srivastava, DK Tosh, A Chinn, KA Jacobson, E Gouaux, ... Biophysical Journal 124 (3), 178a , 2025 2025
BPS2025-Structure of the human dopamine transporter and mechanisms of allosteric inhibition DK Srivastava, V Navratna, DK Tosh, A Chinn, MF Sk, E Tajkhorshid, ... Biophysical Journal 124 (3), 547a , 2025 2025
Dynamic interplay of loop motions governs the molecular level regulatory dynamics in spleen tyrosine kinase: Insights from molecular dynamics simulations S Samanta, MF Sk, S Koirala, P Kar The Journal of Physical Chemistry B 128 (43), 10565-10580 , 2024 2024 Citations: 4
Structure of the human dopamine transporter and mechanisms of inhibition DK Srivastava, V Navratna, DK Tosh, A Chinn, MF Sk, E Tajkhorshid, ... Nature 632 (8025), 672-677 , 2024 2024 Citations: 62
Raw data for: Structure of the human dopamine transporter and mechanisms of allosteric inhibition. MF Sk, E Tajkhorshid Zenodo , 2024 2024
Microsecond dynamics of H10N7 influenza neuraminidase reveals the plasticity of loop regions and drug resistance due to the R292K mutation MF Sk, S Samanta, S Poddar, P Kar Journal of Computational Chemistry 45 (5), 247-263 , 2024 2024 Citations: 8
Deciphering the molecular choreography of Janus kinase 2 inhibition via Gaussian accelerated molecular dynamics simulations: a dynamic odyssey MF Sk, S Samanta, P S, P Kar Journal of Computer-Aided Molecular Design 38 (8) , 2024 2024 Citations: 3
Exploring molecular interactions of potential inhibitors against the spleen tyrosine kinase implicated in autoimmune disorders via virtual screening and molecular dynamics … S Samanta, MF Sk, S Koirala, P Kar SAR and QSAR in Environmental Research 34 (11), 869-897 , 2023 2023 Citations: 7
Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease R Roy, MF Sk, O Tanwar, P Kar Molecular Diversity 27 (4), 1587-1602 , 2023 2023 Citations: 7
Conformational preferences of triantennary and tetraantennary hybrid N-glycans in aqueous solution: Insights from 20 μs long atomistic molecular dynamic simulations R Roy, S Poddar, MF Sk, P Kar Journal of Biomolecular Structure and Dynamics 41 (8), 3305-3320 , 2023 2023 Citations: 8
A Comprehensive Analysis Of The New Education Policy 2020 In India: Implications, Challenges, And Opportunities For Transforming The Education System M Sk, R Rahed, S No Education and Society 47, 122-129 , 2023 2023 Citations: 4
Finding potential inhibitors against RNA-dependent RNA polymerase (RdRp) of bovine ephemeral fever virus (BEFV): an in - silico study S Pyasi, NA Jonniya, MF Sk, D Nayak, P Kar Journal of Biomolecular Structure and Dynamics 40 (20), 10403-10421 , 2022 2022 Citations: 6
Finding inhibitors and deciphering inhibitor-induced conformational plasticity in the Janus kinase via multiscale simulations MF Sk, P Kar SAR and QSAR in Environmental Research 33 (11), 833-859 , 2022 2022 Citations: 9
A plausible contributor to multiple sclerosis; presentation of antigenic myelin protein epitopes by major histocompatibility complexes S Jakhmola, MF Sk, A Chatterjee, K Jain, P Kar, HC Jha Computers in Biology and Medicine 148, 105856 , 2022 2022 Citations: 15
Identification of novel efflux pump inhibitors for Neisseria gonorrhoeae via multiple ligand-based pharmacophores, e-pharmacophore, molecular docking, density functional theory … N Jain, MF Sk, A Mishra, P Kar, A Kumar Computational Biology and Chemistry 98, 107682 , 2022 2022 Citations: 10
Phosphorylation-Induced Conformational Dynamics and Inhibition of Janus Kinase 1 by Suppressors of Cytokine Signaling 1 MF Sk, NA Jonniya, R Roy, P Kar The Journal of Physical Chemistry B 126 (17), 3224–3239 , 2022 2022 Citations: 10
MOST CITED SCHOLAR PUBLICATIONS
Plant-derived natural polyphenols as potential antiviral drugs against SARS-CoV-2 via RNA‐dependent RNA polymerase (RdRp) inhibition: an in-silico analysis S Singh, MF Sk, A Sonawane, P Kar, S Sadhukhan Journal of Biomolecular Structure and Dynamics 39 (16), 6249-6264 , 2020 2020 Citations: 206
Elucidating biophysical basis of binding of inhibitors to SARS-CoV-2 main protease by using molecular dynamics simulations and free energy calculations MF Sk, R Roy, NA Jonniya, S Poddar, P Kar Journal of Biomolecular Structure and Dynamics 39 (10), 3649-3661 , 2020 2020 Citations: 91
Structure of the human dopamine transporter and mechanisms of inhibition DK Srivastava, V Navratna, DK Tosh, A Chinn, MF Sk, E Tajkhorshid, ... Nature 632 (8025), 672-677 , 2024 2024 Citations: 62
Investigating phosphorylation-induced conformational changes in WNK1 kinase by molecular dynamics simulations NA Jonniya, MF Sk, P Kar ACS omega 4 (17), 17404-17416 , 2019 2019 Citations: 57
Identification of Potential Inhibitors against Epstein–Barr Virus Nuclear Antigen 1 (EBNA1): An Insight from Docking and Molecular Dynamic Simulations S Jakhmola, NA Jonniya, MF Sk, A Rani, P Kar, HC Jha ACS Chemical Neuroscience 12 (16), 3060-3072 , 2021 2021 Citations: 51
Computational investigation of structural dynamics of SARS-CoV-2 methyltransferase-stimulatory factor heterodimer nsp16/nsp10 bound to the cofactor SAM MF Sk, NA Jonniya, R Roy, S Poddar, P Kar Frontiers in Molecular Biosciences 7, 590165 , 2020 2020 Citations: 48
Exploring the potency of currently used drugs against HIV-1 protease of subtype D variant by using multiscale simulations MF Sk, R Roy, P Kar Journal of Biomolecular Structure and Dynamics 39 (3), 988-1003 , 2020 2020 Citations: 48
Unraveling the Molecular Mechanism of Recognition of Selected Next-Generation Antirheumatoid Arthritis Inhibitors by Janus Kinase 1 MF Sk, NA Jonniya, R Roy, P Kar ACS Omega 7 (7), 6195–6209 , 2022 2022 Citations: 25
Finding potent inhibitors against SARS-CoV-2 main protease through virtual screening, ADMET, and molecular dynamic simulation studies R Roy, MF Sk, NA Jonniya, S Poddar, P Kar Journal of Biomolecular Structure and Dynamics 40 (14), 6556-6568 , 2022 2022 Citations: 25
Characterizing an allosteric inhibitor-induced inactive state in with-no-lysine kinase 1 using Gaussian accelerated molecular dynamics simulations NA Jonniya, MF Sk, P Kar Physical Chemistry Chemical Physics 23 (12), 7343-7358 , 2021 2021 Citations: 23
Identification of Food Compounds as Inhibitors of SARS-CoV-2 Main Protease Using Molecular Docking and Molecular Dynamics Simulations VH Masand, MF Sk, P Kar, V Rastija, MEA Zaki Chemometrics and Intelligent Laboratory Systems 217, 104394 , 2021 2021 Citations: 21
Mining of Ebola virus genome for the construction of multi-epitope vaccine to combat its infection U Shankar, N Jain, SK Mishra, MF Sk, P Kar, A Kumar Journal of Biomolecular Structure and Dynamics 40 (11), 4815-4831 , 2022 2022 Citations: 20
A comparative study of structural and conformational properties of WNK kinase isoforms bound to an inhibitor: insights from molecular dynamic simulations NA Jonniya, MF Sk, P Kar Journal of Biomolecular Structure and Dynamics 40 (3), 1400-1415 , 2020 2020 Citations: 17
Exploring the energetic basis of binding of currently used drugs against HIV-1 subtype CRF01_AE protease via molecular dynamics simulations MF Sk, NA Jonniya, P Kar Journal of Biomolecular Structure and Dynamics 39 (16), 5892-5909 , 2020 2020 Citations: 16
A plausible contributor to multiple sclerosis; presentation of antigenic myelin protein epitopes by major histocompatibility complexes S Jakhmola, MF Sk, A Chatterjee, K Jain, P Kar, HC Jha Computers in Biology and Medicine 148, 105856 , 2022 2022 Citations: 15
Decoding the Host–Parasite Protein Interactions Involved in Cerebral Malaria Through Glares of Molecular Dynamics Simulations O Indari, MF Sk, S Jakhmola, NA Jonniya, HC Jha, P Kar The Journal of Physical Chemistry B 126 (2), 387-402 , 2022 2022 Citations: 14
Elucidating specificity of an allosteric inhibitor WNK476 among WNK isoforms using molecular dynamic simulations NA Jonniya, MF Sk, P Kar Chemical Biology & Drug Design 98 (3), 405-420 , 2021 2021 Citations: 13
Unraveling the molecular mechanism of recognition of human interferon-stimulated gene product 15 by coronavirus papain-like proteases: A multiscale simulation study R Roy, NA Jonniya, S Poddar, MF Sk, P Kar Journal of Chemical Information and Modeling 61 (12), 6038-6052 , 2021 2021 Citations: 11
Identification of novel efflux pump inhibitors for Neisseria gonorrhoeae via multiple ligand-based pharmacophores, e-pharmacophore, molecular docking, density functional theory … N Jain, MF Sk, A Mishra, P Kar, A Kumar Computational Biology and Chemistry 98, 107682 , 2022 2022 Citations: 10
Phosphorylation-Induced Conformational Dynamics and Inhibition of Janus Kinase 1 by Suppressors of Cytokine Signaling 1 MF Sk, NA Jonniya, R Roy, P Kar The Journal of Physical Chemistry B 126 (17), 3224–3239 , 2022 2022 Citations: 10
