Efficient Monte Carlo Methods for Cyclic Peptides

Examining the meaning of the peptide transfer free energy obtained from blocked (Gly)_n and cyclic-diglycine model compounds

In experiments, the free energy of transferring the peptide group from water to an osmolyte solution is obtained using the transfer free energy of (Gly)_n with the added assumption that a constant incremental change in free energy with n implies that each additional unit makes an independent contribution to the free energy. Here we test this assumption and uncover its limitations. Together with results for cyclic-diglycine, we show that, in principle, it is not possible to obtain a peptide group transfer free energy that is independent of the model system. We calculate the hydration free energ…

Efficient equilibrium sampling of all-atom peptides using library-based Monte Carlo

We applied our previously developed library-based Monte Carlo (LBMC) to equilibrium sampling of several implicitly solvated all-atom peptides. LBMC can perform equilibrium sampling of molecules using the pre-calculated statistical libraries of molecular-fragment configurations and energies. For this study, we employed residue-based fragments distributed according to the Boltzmann factor of the OPLS-AA forcefield describing the individual fragments. Two solvent models were employed: a simple uniform dielectric and the Generalized Born/Surface Area (GBSA) model. The efficiency of LBMC was compar…

Characteristic Temperatures of Folding of a Small Peptide

We perform a generalized-ensemble simulation of a small peptide taking the interactions among all atoms into account. From this simulation we obtain thermodynamic quantities over a wide range of temperatures. In particular, we show that the folding of a small peptide is a multi-stage process associated with two characteristic temperatures, the collapse temperature T_θ and the folding temperature T_f. Our results give supporting evidence for the energy landscape picture and funnel concept. These ideas were previously developed in the context of studies of simplified protein models, and here for…

Aggregate geometry in amyloid fibril nucleation

We present and study a minimal structure-based model for the self-assembly of peptides into ordered beta-sheet-rich fibrils. The peptides are represented by unit-length sticks on a cubic lattice and interact by hydrogen bonding and hydrophobicity forces. By Monte Carlo simulations with >100,000 peptides, we show that fibril formation occurs with sigmoidal kinetics in the model. To determine the mechanism of fibril nucleation, we compute the joint distribution in length and width of the aggregates at equilibrium, using an efficient cluster move and flat-histogram techniques. This analysis, base…

A library-based Monte Carlo technique enables rapid equilibrium sampling of a protein model with atomistic components

There is significant interest in rapid protein simulations because of the time-scale limitations of all-atom methods. Exploiting the low cost and great availability of computer memory, we report a Monte Carlo technique for incorporating fully flexible atomistic protein components (e.g., peptide planes) into protein models without compromising sampling speed or statistical rigor. Building on existing approximate methods (e.g., Rosetta), the technique uses pre-generated statistical libraries of all-atom components which are swapped with the corresponding protein components during a simulation. T…

使用蒙特卡罗模拟计算反应-扩散系统中的宏观反应速率

Computing macroscopic reaction rates in reaction-diffusion systems using Monte Carlo simulations

本文提出一种基于蒙特卡罗模拟的数值方法，通过事件计数统计直接计算反应-扩散系统中的宏观反应速率，并在多个模型上验证，揭示了微观概率与宏观速率间的粗粒化关系。