Continuously Develop Enhanced Sampling Method

Through adding a harmonic boost potential to smooth the system potential energy surface, Gaussian accelerated molecular dynamics (GaMD) provides enhanced sampling and free energy calculation of biomolecules without the need of predefined reaction coordinates. We are continuously working on improving the acceleration power and energy reweighting of the GaMD by combining the GaMD with replica exchange or other algorithms.

• Ref: Huang YM, McCammon JA, and Miao Y, JCTC (2018), 14, 1853

Coarse-grained and Brownian Dynamics Modeling of Surface Diffusion

A variety of biomolecular interactions can be described as surface reactions, represented as a reactive species embedded on a surface and a ligand that can freely diffuse in the 3D half-space. Such systems include, for example, surface-anchored enzymes, membrane proteins, and receptors on a cell or virus surface. To simulate this surface reaction, one can use an atomically-detailed model to describe the interaction between a receptor and a ligand. Brownian dynamics simulations, calculated according to the overdamped Langevin equation, have been broadly applied to map the kinetic properties of such biomolecular reactions. However, the simulations are time-consuming when the system in question is complex. In this work, we aim to reduce the computational cost of a surface reaction study by constructing a coarse-grained model on the reacting surface.

Understand Molecular Mechanisms of Ligand Binding to p38 Kinase

A protein kinase, p38α mitogen-activated kinase, is of interest as a drug target. The p38 plays a crucial role in regulating the production of proinflammatory cytokines. We are dissecting drug-like molecule association to the p38 through enhanced sampling methods. The study will pursue these aims:

1. Understand the insight mechanisms that may result in different kinetics between DFG-in and DFG-out ligands

2. Identify DFG-out binding modes of type I inhibitor

3. Clarify protein-ligand interaction surface in the association processes

• Ref: Huang YM and Chang C-eA, Biophys J (2012) 103, 342

Toxicity of BP-1 and Its Derivatives to Androgen Receptor

2,4-Dihydroxybenzophenone (BP-1) is a degradation product from diverse commercial materials, e.g., sunscreen. It is a potential endocrine disruptor. Androgen receptor (AR), a type of nuclear receptor that is activated by binding any of the androgenic hormones, has been noticed as a potential target of BP-1. In this work, we aim to identify the binding mode between AR and BP-1. The products from the chlorination of BP-1 will also be discussed in the research. Through molecular dynamics and docking simulations, we will elucidate the toxicity of BP-1 and its derivatives to AR.

Ligand Association to HIV Protease

In this work, we used unbiased all-atom molecular dynamics simulations with an explicit solvent model to study the association processes of protein–ligand binding. Using the protein–ligand systems of HIV protease (HIVp)–xk263 and HIVp–ritonavir as cases, we observed that ligand association is a multi-step process involving diffusion, localization, and conformational rearrangements of the protein, ligand and water molecules. Moreover, these two ligands preferred different routes of binding, which reflect two well-known binding mechanisms: induced-fit and conformation selection models.

• Ref: Miao Y, Huang YM, ..., and Chang C-eA, Biochem (2018), 57, 1533

• Ref: Huang YM, ..., and Chang C-eA, Biochem (2017) 56, 1311

• Ref: Huang YM, Kang M, and Chang C-eA, J Mol Recognit (2014), 27, 537

Brownian Dynamic Study of Time-consuming Diffusion Process

Brownian dynamics is a computational simulation technique used to model the diffusional encounter of two molecules in solution. Here, we applied the method to explore two time-consuming diffusional processes: substrate binding to a protein and intermediate channeling among enzymes. The objective of the former study is to understand the details of molecular encounter that may play a role in the efficient operation of the cAMP signaling apparatus which is terminated by phosphodiesterases. The latter study focuses on the mechanistic basis of oxaloacetate channeling within possible malate dehydrogenase – citrate synthase metabolons that have different structural orientations in their complexes.

• Ref: Huang YM, ..., and McCammon JA, Protein Sci (2018), 27, 463

• Ref: Huang YM, ..., and McCammon JA, Protein Sci (2015), 24, 1884

Antibiotic Discovery Targeting the MlaC Protein in Gram-negative Bacteria

To maintain the lipid asymmetry of the cell envelope in Gram-negative bacteria, the MlaC protein serves as a lipid-transfer factor and delivers phospholipids from the outer to the inner membrane. A strategy of antibiotic discovery is to design a proper compound that can tightly bind to the MlaC protein and inhibit the MlaC function. In this work, we performed molecular dynamics simulations on apo and phospholipid-bound systems to study the dynamical properties of the MlaC. By using the structures from the simulations, we then executed virtual screening to identify potential MlaC binders.

• Ref: Huang YM, ..., McCammon JA, Chem. Biol. Drug Des (2019), 93, 647

• Ref: Huang YM, ..., and McCammon JA Protein Sci (2016), 25, 1430

Protonation States and Catalysis of Tryptophan Synthase Enzyme

Bacterial tryptophan synthase (TRPS) is an enzyme that catalyzes the last two steps in the synthesis of L-tryptopha. It has recently been implicated as a drug target in the development of infectious diseases and herbicides. In the TRPS catalysis, proton transfer serves a foundation in acid-base reactions. Guided by information from solid-state NMR spectroscopy, the primary objective of this work is to elucidate how the position of a single proton on the reacting substrate or cofactor affects local and global protein dynamics during the catalytic cycle.

• Ref: Huang YM, ..., and Chang CA, Protein Sci (2016), 25, 166

• Ref: Chang CA, Huang YM, Mueller LJ, ..., Catalysts (2016), 6, 82

• Ref: Caulkins BG, ..., Mueller LJ, J. Am. Chem. Soc. (2014), 136, 12824

Dynamic Study of Phosphopeptide-binding Domains

Phosphopeptide-binding domains mediate many vital cellular processes. Here, we studied two well-known domains, which are important for signal transduction: BRCT repeats and forkhead-associated (FHA) domain. The work investigated the energies and thermodynamic information of intermolecular interactions between the domains and peptides by using molecular dynamics and Brownian dynamics simulations. Our work explained how the signaling domains can bind to more than one peptide sequence and how the domains create promiscuity from precision.

• Ref: Huang YM and Chang CA, PLoS ONE (2014), e98291

• Ref: Huang YM, ..., and Chang CA, J. Phys. Chem. B (2012), 116, 10247

• Ref: Huang YM and Chang CA, BMC Biophysics (2011), 4, 12