GHOSH MOULICK, A. | bioRxiv Science

bioRxiv2025

Structure-Preserving Coarse-Grained Simulationof Proteins in Explicit Solvent

Many biologically relevant processes occur on time and length scales which are far beyond the reach of atomistic simulations. These processes include large protein dynamics and the self-assembly of biological materials. Coarse-grained molecular modeling allows computer simulations on length and time scales 2-3 orders of magnitude larger than atomistic simulations, bridging the gap between the atomistic and mesoscopic scales. However, the structural information involving the dihedral angles is lost in coarse-graining. We develop a simple coarse-grained protein model with structural information in explicit solvent. We represent the center of mass of each residue as a polymer bead and water oxygen as a solvent bead. Each polymer bead has five degrees of freedom: position of the center and two additional variables for the backbone dihedral angles. All interaction parameters for bonded, non-bonded, dihedral coupling and bead-solvent interactions are derived from the equilibrated all-atom molecular dynamics simulation trajectory. We find that our coarse-grained approach reproduces residue-level structural information that closely matches the crystal structures and all-atom simulation results.

biophysics↗

bioRxiv2022

Conformational fluctuations in molten globule state of α-lactalbumin

Molten globule (MG) state is an intermediate state of protein observed during folding into native structure. MG state of protein is induced by various denaturing agent (like Urea), extreme pH, pressure and heat. Experiments suggest that MG state of some protein is functionally relevant even if there is no well-defined tertiary structure. Earlier experimental and theoretical studies suggest that MG state of the protein is dynamic in nature, where conformational states are interconverted in nanosecond time scales. These observations lead us to study and compare conformational fluctuations of MG state to those of intrinsic disordered protein (IDP). We consider -Lactalbumin(aLA) protein, which shows MG state at low pH upon removal of calcium (Ca2+) ion. We use constant pH molecular dynamics simulation (CpHMD) to maintain low pH during simulation. We use the dihedral principal component analysis, the density based clustering method and the machine learning technique to identify the conformational fluctuations. We observe metastable states in the MG state. The residues containing the essential coordinates responsible for metastability belong to stable helix in crystal structure, but most of them prefer unstructured or bend conformation in MG state. These residues control the exposure of the putative binding residues for fatty acids. Thus, the MG state of protein behaves as intrinsic disorder protein, although the disorder here is induced by external conditions.

biophysics↗