Biomedical subjects

Nitin Rathore

Publications and source records attributed to Nitin Rathore.

6 recordsLinked to original sources

PubMed2006

Thermodynamic stability of beta-peptide helices and the role of cyclic residues.

Beta-peptides are emerging as an attractive class of peptidomimetic molecules. In contrast to naturally occurring alpha-peptides, short oligomers of beta-amino acids (comprising just 4-6 monomers) exhibit stable secondary structures that make them amenable for quantitative, concerted experimental and theoretical studies of the effects of particular chemical interactions on structure. In this work, molecular simulations are used to study the thermodynamic stability of helical conformations formed by beta-peptides containing varying proportions of acyclic (beta(3)) and cyclic (ACH) residues. More specifically, several beta-peptides differing only in their content of cyclic residues are considered in this work. Previous computational studies of beta-peptides have relied mostly on energy minimization of molecular dynamics simulations. In contrast, our study relies on density-of-states based Monte Carlo simulations to calculate the free energy and examine the stability of various folded structures of these molecules along a well-defined order parameter. By resorting to an expanded-ensemble formalism, we are able to determine the free energy required to unfold specific molecules, a quantity that could be measured directly through single-molecule force spectroscopy. Simulations in both implicit and explicit solvents have permitted a systematic study of the role of cyclic residues and electrostatics on the stability of secondary structures. The molecules considered in this work are shown to exhibit stable H-14 helical conformations and, in some cases, relatively stable H-12 conformations, thereby suggesting that solvent quality may be used to manipulate the hydrogen-bonding patterns and structure of these peptides.

Amino Acids↗

PubMed2005

Confinement effects on the thermodynamics of protein folding: Monte Carlo simulations.

The effects of chaperonin-like cage-induced confinement on protein stability have been studied for molecules of varying sizes and topologies. Minimalist models based on Gō-like interactions are employed for the proteins, and density-of-states-based Monte Carlo simulations are performed to accurately characterize the thermodynamic transitions. This method permits efficient sampling of conformational space and yields precise estimates of free energy and entropic changes associated with protein folding. We find that confinement-driven stabilization is not only dependent on protein size and cage radius, but also on the specific topology. The choice of the confining potential is also shown to have an effect on the observed stabilization and the scaling behavior of the stabilization with respect to the cage size.

Computer Simulation↗

PubMed2005

Structure and stability of a model three-helix-bundle protein on tailored surfaces.

The interaction of protein molecules with surfaces is important in numerous applications. Theoretical work on protein adsorption has been limited. In particular, it is difficult to obtain quantitative predictions about the structure and stability of proteins on surfaces. In this study, density-of-states-based simulations were performed on a Gō-like model of a three-helix-bundle fragment from protein A (PDB ID: 1bdd). Both mechanical and thermal stability were investigated on neutral and attractive surfaces and compared to that in the absence of a surface. It was found that attaching the peptide to any type of surface decreases its melting temperature by as much as 9 K, depending upon orientation. Calorimetric cooperativity, as measured by van't Hoff to calorimetric enthalpy ratios, similarly decreased. It was also found that the mechanical strength of the peptide attached to surfaces is degraded to varying extents, depending upon the surface type and protein orientation. A comparison of mechanical and thermal stability showed that the two are not synonymous, but occur through different pathways, and that system configurations that are more thermally stable are not always so mechanically.

Adsorption↗

PubMed2005

Optimal allocation of replicas in parallel tempering simulations.

We have studied the efficiency of parallel tempering simulations for a variety of systems including a coarse-grained protein, an atomistic model polypeptide, and the Lennard-Jones fluid. A scheme is proposed for the optimal allocation of temperatures in these simulations. The method is compared to the existing empirical approaches used for this purpose. Accuracy associated with the computed thermodynamic quantities such as specific heat is also computed and their dependence on the trial-exchange acceptance rate is reported.

Bacterial Proteins↗

PubMed2004

Molecular simulation of the reversible mechanical unfolding of proteins.

In this work we have combined a Wang-Landau sampling scheme [F. Wang and D. Landau, Phys. Rev. Lett. 86, 2050 (2001)] with an expanded ensemble formalism to yield a simple and powerful method for computing potentials of mean force. The new method is implemented to investigate the mechanical deformation of proteins. Comparisons are made with analytical results for simple model systems such as harmonic springs and Rouse chains. The method is then illustrated on a model 15-residue alanine molecule in an implicit solvent. Results for mechanical unfolding of this oligopeptide are compared to those of steered molecular dynamics calculations.

Alanine↗

PubMed2003

Configurational temperature density of states simulations of proteins.

A novel method has been implemented to compute the density of states of proteins. A united atom representation and the CHARMM (Brooks et al., 1983) force-field parameters have been adopted for all the simulations. In this approach, an intrinsic temperature is computed based on configurational information about the protein. A random walk is performed in potential energy space and the configurational temperature is collected as a function of potential energy of the system. The density of states is then calculated by integrating the reciprocal of temperature. Unlike previously available methods, this approach does not involve calculations based on histograms of stochastic visits to distinct energy states. It is found that the proposed method is more efficient than earlier, related schemes for simulation of protein folding. Furthermore, it directly provides thermodynamic information, including free energies. The usefulness of the method is discussed by presenting results of simulations of the 16-residue beta-hairpin taken from the C-terminal fragment (41-56) of protein G.

Algorithms↗