Buffed energy landscapes: Another solution to the kinetic paradoxes of protein folding

TL;DR

This paper introduces a new class of protein energy landscapes called 'buffed' landscapes, characterized by low kinetic barriers and trap removal, expanding the understanding of protein folding mechanisms beyond traditional funnel-shaped landscapes.

Contribution

It demonstrates that proteins can fold efficiently on buffed landscapes with low kinetic barriers, challenging the exclusive focus on funnel-shaped energy landscapes in folding studies.

Findings

Buffed landscapes have low kinetic barriers facilitating folding.

Funneling remains the dominant mechanism for foldability.

Analytical and numerical methods support the viability of buffed landscapes.

Abstract

The energy landscapes of proteins have evolved to be different from most random heteropolymers. Many studies have concluded that evolutionary selection for rapid and reliable folding to a given structure that is stable at biological temperatures leads to energy landscapes having a single dominant basin and an overall funnel topography. We show here that, while such a landscape topography is indeed a sufficient condition for folding, another possibility also exists, giving a new class of foldable sequences. These sequences have landscapes that are only weakly funneled in the conventional thermodynamic sense, but have unusually low kinetic barriers for reconfigurational motion. Traps have been specifically removed by selection. Here we examine the possibility of folding on these "buffed" landscapes, by mapping the determination of statistics of pathways for the heterogeneous nucleation processes involved in escaping from traps to the solution of an imaginary time Schroedinger equation. This equation is solved analytically in adiabatic and ``soft-wall'' approximations, and numerical results are shown for the general case. The fraction of funneled vs. buffed proteins in sequence space is estimated, suggesting the statistical dominance of the funneling mechanism for achieving foldability.