Infinitely Dilute Partial Molar Properties of Peptides and Proteins from Computer Simulation

Abstract

A detailed understanding of temperature and pressure effects on an infinitely dilute solute's conformational equilibrium requires knowledge of infinitely dilute partial molar properties. Established molecular dynamics methodologies generally have not provided a way to calculate these properties without either a loss of thermodynamic rigor, the introduction of non-unique parameters, or a loss of information about which solute conformations specifically contributed to the output values. Here we describe a method that is simple in execution and possesses none of the above disadvantages. We use it to calculate the infinitely dilute partial molar internal and kinetic energies, enthalpy, volume, isothermal compressibility, heat capacity, and thermal expansion coefficient for two proteins, pancreatic trypsin inhibitor and lysozyme. Further, we test the method's performance, in light of currently accessible simulation timescales, to precisely distinguish the thermodynamic differences between a native and denatured conformation of the trp-cage miniprotein. We conclude that those properties corresponding to fluctuating quantities (e.g., partial molar compressibility, thermal expansion coefficient, and heat capacity) will be computationally demanding to calculate precisely, but the other properties (e.g., partial molar volume and enthalpy) can be calculated with the computational power widely available to the community today. The ability to assign properties to specific conformations is a major advantage of our approach.