Research Overview
Our research operates at the intersection of computational molecular biophysics, theoretical physical chemistry, and data science. We design and apply advanced computational approaches — grounded in statistical mechanics, molecular thermodynamics, and machine learning — to problems where molecular dynamics controls biology and function. A defining feature of our group is the co-development of novel in-house algorithms alongside their application to real biological systems.
On the methods side, we develop and release in-house algorithms — PathGennie (direction-guided adaptive sampling for rapid rare-event pathway generation), WeTICA and CoWERA (directed weighted-ensemble enhanced sampling for rare-event kinetics), IceCoder (variational-autoencoder identification of crystal/ice phases), and PPIscout (mixed-solvent mapping of protein–protein interaction hotspots). On the applications side, our work spans dynamic protein allostery and cellular signalling; druggable cryptic-pocket discovery and protein–protein-interaction inhibition (PCSK9, PLK1, Rho GTPases); prion misfolding and aggregation; enzyme promiscuity and selective inhibition (laccase, acetylcholinesterase); the structure of water around solutes and interfaces; and the molecular thermodynamics of soft matter — gas hydrates, designer ionic liquids, self-assembly and nucleation.
Allostery, Signalling & Protein–Protein Interactions
We decode how proteins relay signals between distant sites — the basis of cellular regulation and a powerful, selective handle for drug design. Combining all-atom and mixed-solvent molecular dynamics with QM/MM, we established the electrostatics-driven, dynamic nature of allostery in PDZ domains, mapped nucleotide- and phosphorylation-controlled switching in Rho-family GTPases, and uncovered druggable cryptic pockets that let us inhibit otherwise ‘undruggable’ protein–protein interactions such as PCSK9–LDLR and PLK1.
Selected Publications
- Nucleotide dependent switching in rho GTPase: conformational heterogeneity and competing molecular interactions
- Hidden electrostatic basis of dynamic allostery in a PDZ domain
- Protonation-induced dynamic allostery in PDZ domain: evidence of perturbation-independent universal response network
- Phosphorylation-Competent Metastable State of Escherichia coli Toxin HipA
- Molecular mechanism of regulation of RhoA GTPase by phosphorylation of RhoGDI
- Leveraging Bidirectional Nature of Allostery To Inhibit Protein–Protein Interactions (PPIs): A Case Study of PCSK9–LDLR Interaction
- Unraveling antibody‐induced mechanical stability of antigen: Insights from single‐molecule studies
- Harnessing Allostery to Modulate Protein-Protein Interactions: From Function to Therapeutic Innovations
- Mixed-Solvent Molecular Dynamics Simulation Reveals a Druggable Allosteric Pocket in the PCSK9 C-Terminal Domain
- Phosphorylation induces altered protonation states and allosterically regulates Rac1–RhoGDI complex
- Mapping Protein–Protein Interaction Hotspots and Unveiling a Cryptic Allosteric Pocket in PLK1 PBD via Mixed-Solvent Molecular Dynamics
Enhanced Sampling & Machine Learning
A defining feature of our group is the co-development of new in-house algorithms alongside their application. We build enhanced-sampling and machine-learning methods that break the timescale and dimensionality barriers of molecular simulation: directed weighted-ensemble samplers (WeTICA, CoWERA), rapid rare-event pathway generators (PathGennie), variational-autoencoder classifiers of physical states (IceCoder), and mixed-solvent interaction-hotspot mappers (PPIscout).
Selected Publications
- Support vector regression-based Monte Carlo simulation of flexible water clusters
- IceCoder: Identification of Ice phases in molecular simulation using variational autoencoder
- Mapping conformational landscape in protein folding: Benchmarking dimensionality reduction and clustering techniques on the Trp-Cage mini-protein
- WeTICA: A directed search weighted ensemble based enhanced sampling method to estimate rare event kinetics in a reduced dimensional space
- PathGennie: Rapid Generation of Rare Event Pathways via Direction-Guided Adaptive Sampling Using Ultrashort Monitored Trajectories
- PPIscout: Protein–protein interaction site hotspot mapping using mixed amino acid–water molecular dynamics simulation
- CoWERA: A temporal coherence guided binless resampling algorithm for weighted-ensemble based estimation of rare-event kinetics
Folding, Misfolding & Enzyme Catalysis
We connect molecular structure and dynamics to biological function — and dysfunction. Our simulations resolve how prion proteins misfold and aggregate into disease-associated states, how mini-proteins navigate their folding landscapes, and how enzymes such as laccase achieve broad substrate promiscuity or are selectively inhibited (acetylcholinesterase) — bridging fundamental biophysics with bioremediation and drug discovery.
Selected Publications
- Replica exchange molecular dynamics study of dimerization in prion protein: multiple modes of interaction and stabilization
- Mechanism of unfolding of human prion protein
- Temperature-induced misfolding in prion protein: evidence of multiple partially disordered states stabilized by non-native hydrogen bonds
- Organoselenium compounds as acetylcholinesterase inhibitors: Evidence and mechanism of mixed inhibition
- Molecular Thermodynamic Origin of Substrate Promiscuity in the Enzyme Laccase: Toward a Broad-Spectrum Degrader of Dye Effluents
- Elucidating the molecular mechanism of noncompetitive inhibition of acetylcholinesterase by an antidiabetic drug chlorpropamide: identification of new allosteric sites
Water, Hydration & Solvation
Water is an active participant in molecular recognition, not a passive backdrop. We quantify the length-scale–dependent structure and dynamics of water around hydrophobic solutes and interfaces, in nanoconfinement (reverse micelles, membrane-protein channels) and in mixed solvents — and connect these microscopic pictures directly to spectroscopic observables such as 2D-IR and vibrational Stark probes.
Selected Publications
- Structural order of water molecules around hydrophobic solutes: Length-scale dependence and solute–solvent coupling
- Exploration of the presence of bulk-like water in AOT reverse micelles and water-in-oil nanodroplets: the role of charged interfaces, confinement size and properties of water
- Correlating nitrile IR frequencies to local electrostatics quantifies noncovalent interactions of peptides and proteins
- Two-Dimensional Infrared Spectroscopy Reveals Cosolvent-Composition-Dependent Crossover in Intermolecular Hydrogen-Bond Dynamics
- Electrostatic Origin of the Red Solvatochromic Shift of DFHBDI in RNA Spinach
- Structural and dynamical heterogeneity of water trapped inside Na+-pumping KR2 rhodopsin in the dark state
- Size-Dependent Order–Disorder Crossover in Hydrophobic Hydration: Comparison between Spherical Solutes and Linear Alcohols
- How Far Is “Bulk Water” from Interfaces? Depends on the Nature of the Surface and What We Measure
Soft Matter, Self-Assembly & Interfaces
We apply molecular thermodynamics to complex, real-world soft-matter systems: the nucleation and growth of gas (methane) hydrates relevant to energy and flow assurance, designer ionic liquids that stabilise biomolecules, surfactant and polymer self-assembly, nanoparticle nucleation, and stimuli-responsive liquid crystals — frequently in close partnership with experiment and industry.
Selected Publications
- Effect of the amino acid l-histidine on methane hydrate growth kinetics
- Partially bio‐based poly (amide imide) s by polycondensation of aromatic diacylhydrazides based on lignin‐derived phenolic acids and aromatic dianhydrides: Synthesis …
- Molecular View of CO2 Capture by Polyethylenimine: Role of Structural and Dynamical Heterogeneity
- Effect of sodium dodecyl sulfate surfactant on methane hydrate formation: a molecular dynamics study
- Critical assessment of the interaction between DNA and choline amino acid ionic liquids: evidences of multimodal binding and stability enhancement
- Amino-acid-based ionic liquids for the improvement in stability and activity of cytochrome c: A combined experimental and molecular dynamics study
- Macro and Molecular Level Insights on Gas Hydrate Growth in the Presence of Hofmeister Salts
- Morphology and dynamics of self-assembled structures in mixed surfactant systems (SDS+ CAPB) in the context of methane hydrate growth
- Heterogeneous nucleation in citrate synthesis of AgNPs: Effect of mixing and solvation dynamics
- Molecular Insight into Dye–Surfactant Interaction at Premicellar Concentrations: A Combined Two-Photon Absorption and Molecular Dynamics Simulation Study
- Dimer-parity-dependent odd-even effects in photoinduced transitions to cholesteric and twist grain boundary smectic- mesophases: Experiments and simulations
- Efficient light harvesting in self-assembled organic luminescent nanotubes