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2081, 2086, 2094, 2097, 2105, 2124, 2165, 2172, 2190, 2222, 2243, 2261, 2311, 2332, 2351, 2364, 2376, 2394, 2435, 2492, 2518, 2531, 2544, 2571, 2634, 2642, 2672, 2683, 2695, 2751, 2791, 2809, 2866, 2930, 3148, 3351, 3429, 3544, 3560, 3584, 3663, 3692, 3712, 3722, 3891, 3905, 3954, 4022, 4074, 4088, 4094, 4108, 4110], 'Conditions': [171, 194, 2034], 'Use': [173], 'check': [175], 'box': [176], 'below': [177, 200, 1285], 'share': [179, 202, 4005], 'version': [181, 205], 'article.I': [183], 'have': [184, 234, 419, 584, 737, 749, 1266, 1290, 1322, 1828, 2227, 2802, 2908, 2962, 2996, 3060, 3331, 3434, 3444, 3529, 3609, 3634, 3689, 3693, 3718, 3730, 3886, 3894], 'read': [185], 'accept': [187], 'the': [188, 198, 243, 249, 275, 288, 301, 309, 325, 334, 350, 353, 357, 381, 399, 431, 440, 467, 487, 502, 511, 524, 534, 538, 556, 559, 575, 578, 589, 606, 609, 615, 620, 630, 646, 654, 668, 681, 688, 696, 726, 806, 824, 840, 870, 886, 890, 904, 912, 917, 920, 949, 1010, 1024, 1035, 1053, 1057, 1068, 1080, 1083, 1087, 1093, 1096, 1104, 1111, 1117, 1133, 1149, 1167, 1171, 1181, 1211, 1219, 1225, 1231, 1239, 1245, 1269, 1281, 1356, 1379, 1389, 1398, 1417, 1424, 1433, 1451, 1466, 1496, 1502, 1508, 1513, 1517, 1524, 1529, 1541, 1553, 1593, 1613, 1627, 1685, 1691, 1712, 1718, 1737, 1757, 1765, 1803, 1809, 1812, 1838, 1847, 1855, 1860, 1875, 1878, 1884, 1891, 1906, 1909, 1944, 1949, 1969, 2001, 2004, 2023, 2037, 2049, 2056, 2073, 2076, 2084, 2100, 2113, 2121, 2130, 2137, 2166, 2178, 2188, 2195, 2204, 2207, 2213, 2235, 2266, 2273, 2282, 2303, 2380, 2384, 2391, 2398, 2412, 2421, 2445, 2459, 2465, 2469, 2484, 2493, 2541, 2564, 2567, 2574, 2579, 2590, 2614, 2629, 2647, 2658, 2677, 2680, 2684, 2686, 2696, 2703, 2722, 2725, 2731, 2739, 2743, 2755, 2768, 2811, 2816, 2820, 2843, 2870, 2874, 2885, 2926, 2940, 2952, 2958, 2973, 2979, 2989, 3004, 3007, 3015, 3019, 3056, 3089, 3127, 3141, 3152, 3165, 3178, 3183, 3188, 3194, 3198, 3205, 3208, 3242, 3261, 3286, 3295, 3299, 3307, 3360, 3366, 3370, 3404, 3419, 3456, 3513, 3519, 3533, 3540, 3554, 3572, 3604, 3617, 3624, 3643, 3677, 3699, 3733, 3740, 3746, 3752, 3762, 3770, 3783, 3809, 3815, 3833, 3853, 3861, 3868, 3873, 3902, 3934, 3995, 4017, 4035, 4051, 4054, 4068, 4075], 'Wiley': [189, 365, 4201, 4262, 4297, 4739, 4756, 4778, 4810], 'Online': [190, 4202, 4263, 4298, 4740, 4757, 4779, 4811], 'Library': [191], 'UseShareable': [196], 'LinkUse': [197], 'link': [199], 'a': [203, 218, 225, 319, 443, 452, 458, 565, 585, 597, 692, 699, 760, 780, 835, 900, 955, 997, 1048, 1060, 1065, 1125, 1139, 1146, 1164, 1191, 1205, 1256, 1273, 1307, 1428, 1472, 1548, 1560, 1570, 1617, 1648, 1694, 1745, 1783, 1832, 1900, 1919, 2231, 2253, 2277, 2452, 2482, 2548, 2554, 2749, 2839, 2858, 2933, 2984, 3001, 3061, 3124, 3138, 3149, 3218, 3230, 3247, 3254, 3274, 3336, 3348, 3386, 3400, 3435, 3445, 3469, 3484, 3495, 3536, 3557, 3680, 3800, 3919, 3970, 3975, 3981], 'article': [208], 'with': [209, 308, 514, 636, 676, 733, 746, 789, 800, 919, 934, 1090, 1145, 1244, 1388, 1456, 1465, 1475, 1666, 1697, 1721, 1762, 1782, 1786, 1905, 1932, 1979, 2010, 2150, 2429, 2432, 2437, 2458, 2557, 2861, 2957, 2970, 3023, 3033, 3050, 3119, 3298, 3327, 3425, 3441, 3471, 3479, 3490, 3504, 3630, 3650, 3684, 3695, 3709, 3983, 4000, 4039, 4063], 'your': [210], 'friends': [211], 'colleagues.': [213], 'Learn': [214], 'more.Copy': [215], 'URL': [216], 'Share': [217], 'linkShare': [219], 'onFacebookTwitterLinked': [220], 'InRedditWechat': [221], 'Abstract': [222], 'Proteins': [223, 4196, 4751, 4770], 'exhibit': [224], 'nonuniform': [226, 289, 727], 'structures.': [229, 361, 603, 754, 1384, 3394, 3566, 3626, 3652, 3774, 3941], 'A': [230, 414], 'number': [231, 415, 433, 468, 1467, 1687, 1771, 1833, 3497], 'models': [233, 418, 1262, 1347, 1578], 'been': [235, 264, 283, 386, 420, 546, 581, 1267, 1829, 3101, 3502, 3887], 'advanced': [236, 421, 3660], 'explain': [238, 423], 'observation': [240], 'considering': [242, 428, 1003, 1423], 'designabilities,': [246, 2630, 2685, 3697], 'that': [247, 254, 266, 287, 436, 471, 476, 485, 496, 523, 713, 748, 823, 909, 928, 972, 1056, 1124, 1193, 1242, 1337, 1404, 1407, 1574, 1844, 1868, 1916, 1954, 2157, 2379, 2852, 2925, 2995, 3014, 3029, 3039, 3168, 3232, 3260, 3270, 3294, 3325, 3333, 3359, 3461, 3468, 3517, 3570, 3581, 3646, 3667, 3732, 3789, 3795, 3881], 'is,': [248, 1455], 'fraction': [250, 1738, 1892, 2841], 'all': [252, 390, 947, 969, 1214, 1401, 1449, 1586, 1655, 1710, 1894, 1923, 1952, 1978, 2405, 2792, 2800, 2882, 2992], 'sequences': [253, 435, 470, 495, 513, 685, 950, 992, 1144, 1371, 1403, 1453, 1587, 1641, 1714, 1720, 1740, 1753, 1760, 1843, 1867, 1897, 1915, 1953, 1975, 2406, 2747, 2760, 2793, 2801, 2844, 2994, 3016, 3022, 3032, 3047, 3117, 3136, 3408, 3883, 4029], 'could': [255, 461, 490, 506, 1176, 1778, 3201, 3946], 'successfully': [256, 473], 'fold': [257, 474, 976, 994, 1063, 1131, 3978, 3982, 4056], 'into': [258, 398, 475, 932, 977, 1406, 1899, 1918, 3974, 3980], 'any': [259, 827, 941, 1775, 2853], 'particular': [260, 3169, 3801], 'structure.': [261, 943, 1408, 2197, 2825, 3170], 'It': [262, 3775], 'has': [263, 281, 318, 385, 544, 580, 1543, 2932, 3099, 3501], 'postulated': [265], 'designable': [268, 526, 718, 2486, 3041, 3058, 3073, 3145, 3156, 3599, 3606, 3977, 4028], 'should': [270, 528], 'be': [271, 298, 462, 491, 508, 529, 721, 1128, 1155, 1163, 1178, 1195, 1224, 1328, 1335, 1670, 1780, 2777, 3174, 3202, 3306, 3590, 3594, 3648, 3824, 3856, 3916, 3966], 'common,': [273], 'although': [274], 'exact': [276, 535], 'nature': [277, 296, 536], 'relationship': [280, 400, 539, 607, 1885, 2927, 3541, 4004], 'not': [282, 393, 545, 855, 946, 1491, 1870, 2479, 2867, 2879, 3511, 3885], 'addressed.': [284, 548], 'We': [285, 651, 711, 758, 821, 888, 1235, 2719, 3012, 3186, 3729, 3957, 4008, 4081], 'find': [286, 712, 1218], 'found': [294], 'can': [297, 736, 929, 1194, 1209, 1236, 1334, 2907, 3528, 3647], 'explained': [299, 3203], 'interplay': [302], 'evolution': [304, 571, 634, 1360, 1421, 1610, 1970, 1988, 2389, 2786, 2832, 3839, 3866, 3962, 4015, 4036], 'population': [306, 579, 672, 700, 714, 1282, 1618, 1635, 1692, 1813, 2024, 2087, 2106, 2312, 2388, 2460, 2502, 2581, 2620, 2635, 2655, 2704, 2785, 2831, 2913, 2960, 3199, 3263, 3290, 3302, 3390, 3437, 3447, 3547, 3727, 3757], 'dynamics': [307, 631, 697, 1614, 1791, 2168, 2180, 2741, 2914, 3200, 3303], 'designability': [310, 541, 640, 664, 1365, 1390, 1907, 2283, 2348, 2466, 2515, 2591, 2931, 3166, 3350, 3473, 3543, 3559], 'distribution.': [311], 'relative': [313, 432, 610, 621, 2046, 2131, 2267, 2381, 2415, 2812, 2817, 3284], 'frequency': [314, 543, 648], 'different': [316, 739, 1324, 2006, 2077, 2726, 2829, 3393, 3410, 4065], 'greater-than-linear': [320], 'dependence': [321, 2454, 2942], 'on': [322, 588, 810, 860, 899, 1013, 1116, 1295, 1626, 1943, 2136, 2209, 2716, 2912, 2945, 3054, 3177, 3365, 3455, 3623, 3798], 'designability,': [323, 2236], 'making': [324, 1280], 'observed': [328, 532, 1837, 3196, 3297, 3503, 3939], 'uneven': [332, 375, 425], 'than': [333, 1138, 1506, 1522, 2420, 2498, 2968, 3048, 3269, 3487, 3745, 3979], 'designabilities.': [337, 730, 3052], 'is': [342, 555, 605, 832, 845, 869, 971, 995, 1064, 1103, 1136, 1534, 1550, 1567, 1852, 1962, 2256, 2417, 2442, 2451, 2553, 2578, 2589, 2781, 2828, 2848, 2878, 3217, 3267, 3282, 3342, 3374, 3385, 3402, 3412, 3510, 3535, 3550, 3602, 3759, 3776, 3931, 3987, 4046], 'also': [343, 3100, 3323, 3413, 4010], 'affected': [344, 666], 'additional': [346], 'factors': [347, 625, 637], 'such': [348, 638, 3993], 'as': [349, 639, 1073, 1397, 1569, 1682, 1684, 1890, 2244, 2289, 2291, 2585, 2626, 2736, 2738, 2988, 3000, 3071, 3123, 3396, 3423, 3737, 3739, 3827, 3879, 3888, 3918, 3949, 3963, 3994], 'topology': [351, 3368], 'sequence': [354, 402, 828, 1126, 1243, 1430, 1443, 1482, 1498, 1531, 1563, 1595, 1663, 1704, 1777, 1848, 2060, 2122, 2139, 2189, 2823, 2854, 2860, 3008, 3209, 3212, 3310, 3371, 3397, 3465, 3516, 3834, 3971, 4020], 'space': [355, 1434, 2123, 2744, 3311, 3771, 4021], 'similarity': [358, 643, 3562], 'other': [360, 624, 752, 3564, 3597, 3641, 3651, 3810], '©': [362], 'John': [364], '&': [366], 'Sons,': [367], 'Inc.': [368], 'Biopoly': [369], '53:': [370], '1–8,': [371], 'INTRODUCTION': [373], 'families': [379], 'among': [380, 531, 1448, 2573, 2603, 3872], 'various': [382, 616, 991, 2050, 2270, 2385, 2575], 'possible': [383, 617, 802, 951, 1215, 2576, 2746, 2883, 3565, 3575, 3625, 3671, 3773, 3874], 'folds': [384, 391, 618, 3875, 3930], 'repeatedly': [387], 'noted.1-5': [388], 'That': [389], 'are': [392, 497, 626, 665, 744, 854, 859, 923, 1152, 1340, 1579, 1588, 1869, 1990, 2026, 2407, 2488, 2504, 2600, 2637, 2665, 2770, 2845, 3026, 3075, 3224, 3235, 3355, 3462], 'equally': [394, 1156], 'represented': [395, 804, 1736, 1781], 'provides': [396, 798, 1272], 'insights': [397], 'between': [401, 455, 540, 608, 683, 873, 1886, 2072, 2455, 2679, 2928, 3392, 3542, 3556, 3612, 3637], 'structure,': [404, 3578], 'important': [405], 'applications': [407], 'both': [409, 3952], 'structure': [410, 460, 1364, 1394, 1901, 1920, 2395, 2595, 3139, 3150, 3401, 3470, 3489, 3754, 3904], 'prediction': [411], 'design.': [413], 'theoretical': [417, 453], '“designability,”': [430], 'would': [437, 472, 2720, 3589, 3608, 3633, 3673, 3965, 4009, 4030, 4082], 'result': [438, 557, 3308, 3534, 3837], 'formation': [441], 'specific': [444, 3367, 3805], 'structure.6-14': [445], 'For': [446, 1512, 1654, 1877, 1922, 1968, 2198], 'instance,': [447], 'Govindarajan': [448, 4090], 'made': [451], 'connection': [454], 'how': [456, 653, 1612, 2264, 3778], 'much': [457, 3779], 'given': [459, 833, 942], 'optimized': [463], 'folding': [465, 1265, 1278, 1297, 1313, 1331, 1898], 'structure.10,': [477], '11': [478, 4303], 'According': [479], 'work,': [482, 1187], 'those': [483, 3030, 3252, 3682, 3707], 'were': [486, 1348, 1462, 1490, 1557, 1600, 1715, 1725, 1792, 1814, 1930, 1976, 2039, 2052, 2079, 2133], 'most': [488, 3514, 3520, 3605], 'optimizable': [489, 504], 'formed': [492, 509, 1405, 1917], 'many': [494, 2430, 3476, 3610, 3635, 3685, 3845], 'far': [498, 3614], 'from': [499, 1034, 1440, 1447, 1471, 1756, 1774, 1946, 2444, 3018, 3031, 3951], 'optimal,': [500], 'while': [501, 2193, 3439], 'less': [503, 1521, 2496, 3057, 3591, 3724], 'only': [507, 3305], 'few': [512, 3669], 'close-to-optimal': [515], 'interactions.': [516, 3908], 'While': [517, 1259], 'it': [518, 1190, 1253, 1333, 3509, 3964], 'seems': [519], 'reasonable': [520], 'presume': [522], 'overrepresented': [530, 753, 2491, 3087], 'proteins,': [533, 678, 954, 3787], 'adequately': [547, 2119], 'current': [550], 'long': [560, 2737, 2772, 3738], 'period': [561], 'evolution,': [563], 'inherently': [564], 'dynamic,': [566], 'nonequilibrium': [567], 'process.': [568], 'In': [569, 741, 944, 1006, 1040, 1185, 1552, 1590, 2128, 2410, 2797, 2920, 3567, 3627], 'addition,': [570], 'occurs': [572], 'populations;': [574], 'role': [576], 'shown': [582, 1336, 2239, 2552, 3238], 'dramatic': [586], 'impact': [587], 'evolutionary': [590, 1292, 1346, 1425, 2167, 2179, 2632, 2740, 2756, 3816, 4003], 'process': [591, 1182, 1767], 'RNA.15': [593], 'Designability,': [594], 'however,': [595, 1304], 'represents': [596, 2939, 3164], 'static': [598], 'property': [599, 965], 'individual': [601, 1866, 2651], 'What': [604, 623], 'rate': [611, 1169, 1735, 1862, 2967, 2982, 3063, 3114, 3354, 3362, 4025], 'occurrence': [613], 'designabilities?': [622], 'important?': [627], 'How': [628], 'do': [629], 'population-based': [633], 'interact': [635], 'structural': [642, 3686, 3720, 3850, 3929], 'affect': [645], "structure's": [647, 3349, 3558], 'nature?': [650], 'consider': [652, 680, 759, 1189], 'results': [655, 1118, 1945, 2002, 2210, 2371, 3943], 'previously': [658], 'developed': [659, 1026], 'computational': [660, 1318, 4098], 'model': [661, 768, 1009, 1354, 1538, 1608, 1630], 'dynamical': [669, 1357], 'aspects': [670, 1358, 1419, 3900, 3937], 'evolution.': [673, 1005, 1184, 3956], 'Using': [674], 'simulations': [675, 1283, 1989, 2025, 2088, 2107, 2114, 2705, 2769, 3505], 'lattice': [677, 795, 862, 1120], 'we': [679, 957, 1022, 1122, 1188, 1208, 1882, 1999, 2155, 2201, 2229, 2923, 3258, 3579, 3945], 'differences': [682, 2903, 3379], 'selecting': [684], 'at': [686, 793, 877, 882, 1372, 1445, 2089, 2108, 3221, 3880], 'random,': [687, 1373], 'random': [689, 706, 1099, 1112, 1446, 1674, 1947, 1973, 2013, 2101, 2274, 2323, 2648, 2750, 2762, 3116, 3135, 3233, 3255], 'walks': [690, 809, 2009, 2763, 3234], 'single': [693, 1429, 2278, 2759], 'protein,': [694], 'proteins': [702, 769, 908, 970, 1016, 1620, 3734, 3871, 3999, 4038, 4062], 'acted': [703], 'upon': [704, 1047, 1802], 'mutations,': [707], 'reproduction,': [708], 'death.': [710], 'effects': [715, 2503], 'cause': [716], 'highly': [717, 761, 1341, 2134, 2485, 3040, 3045, 3072, 3582, 3586, 3598, 3841, 3976, 4027], 'even': [722, 2250, 2489, 3750], 'overrepresented,': [724], 'exaggerating': [725], 'Furthermore,': [731], 'similar': [734, 1871, 3328, 3496, 3595, 3670, 3842, 4006], 'designabilities': [735, 2304, 2396, 2424, 2570, 2690, 2735, 3329, 3481, 3493, 3632, 3691, 3711], 'significantly': [738, 2418], 'occupancies.': [740, 2440], 'particular,': [742, 1041], 'enhanced': [745], 'similarities': [750, 2678], 'METHODS': [755], 'Model': [757], 'simplified': [762], 'representation': [763], 'proteins.': [766, 2796], 'Our': [767, 1983, 3942], 'consist': [770], 'chains': [772], 'n': [774, 1644], '=': [775, 1075, 1583, 1638, 1934, 1985, 2063, 2067, 2091, 2110, 2142, 2287, 2293, 2318, 2337, 2361, 2367, 2402, 2427, 2528, 2534, 2608, 2624, 2663, 2708, 2789, 2950, 3121], '25': [776, 4561], 'monomers,': [777], 'confined': [778, 2183], '5': [781, 783, 4188], '×': [782], 'two-dimensional': [784], 'maximally': [785], 'compact': [786, 979], 'square': [787], 'lattices,': [788], 'each': [790, 1393, 1658, 3162, 3222, 3577, 3640], 'monomer': [791], 'located': [792], 'one': [794, 1369, 1479, 1701, 3932], 'point.': [796], 'This': [797, 1385, 1533, 1566, 2147, 2779, 2938, 3292, 3415, 3601, 3756, 3986], 'us': [799, 1387], '1081': [801, 807], 'conformations': [803, 1216], 'self-avoiding': [808], 'lattice,': [812], 'neglecting': [813], 'related': [815, 4061], 'rotation,': [817], 'reflection,': [818], 'or': [819, 2592], 'inversion.': [820], 'assume': [822, 1123], 'energies': [825, 892, 1109], 'conformation': [830, 865], 'k': [831, 1902], 'simple': [836, 1050], 'contact': [837, 871, 891], 'energy': [838, 872, 1054, 1085, 1212], 'form:': [841], '(1)': [842], 'Here,': [843], 'Δ': [844, 1078], 'equal': [846, 2804], 'if': [849, 1132, 1252, 1501, 1516, 3193, 3751], 'residues': [850, 927, 3613, 3638], 'i': [851, 879], 'j': [853, 884], 'covalently': [856], 'connected': [857], 'but': [858], 'adjacent': [861], 'sites': [863], 'k,': [866, 1395], 'γ(𝒜i𝒜j)': [868], 'amino': [874, 1460, 3906], 'acids': [875, 1461], '𝒜i': [876], 'location': [878, 883], '𝒜j': [881], 'sequence.': [887, 3069], 'use': [889, 1023], 'derived': [893, 1896], 'Miyazawa': [895], 'Jernigan': [897], 'based': [898, 1046, 1294, 1625], 'statistical': [901], 'analysis': [902, 1293], 'database': [905], 'known': [907], 'implicitly': [910], 'includes': [911], 'effect': [913, 2911, 3287, 3549], 'interactions': [915, 2191], 'solvent.16': [921], 'There': [922, 2847], '132': [924], 'pairs': [925], 'possibly': [930], 'come': [931], 'contact,': [933], '16': [935, 4383], 'these': [937, 1338, 1575, 1958, 2176, 2199, 2456, 2598, 2798, 3083], 'contacts': [938, 3611, 3636, 3645], 'present': [939, 3343], 'nature,': [945], 'represent': [952, 2794], 'viable': [953, 1015, 1257, 1402, 1436, 1452, 1562, 1727, 1776, 1914, 1956, 2795, 3028, 3736], 'characteristic': [956], 'must': [958, 3791], 'include': [959], 'model.': [962], 'One': [963, 2560], 'universal': [964], 'shared': [966, 3649], 'essentially': [968], 'they': [973, 3790], 'need': [974, 1019], 'regular,': [978], 'shapes': [980], 'rapidly': [981, 1274], 'enough': [982], 'avoid': [984], 'proteolysis': [985], 'aggregation.': [987], 'ability': [989, 1058], 'obviously': [996], 'constraint': [998], 'great': [1000], 'importance': [1001], 'order': [1007, 3765], 'requirements': [1011], 'placed': [1012], 'biologically': [1014], 'their': [1018, 1375, 2734], 'fold,': [1021], 'approach': [1025], 'Wolynes': [1028, 1042], 'co-workers': [1030, 1044], 'who': [1031, 1836, 3665], 'borrowed': [1032], 'ideas': [1033], 'physics': [1036], 'spin': [1038], 'glasses.17': [1039], 'concluded': [1045, 3666], 'particularly': [1049], 'description': [1051], 'landscape': [1055], 'function': [1066, 1165, 3002, 3125], "protein's": [1069], '“foldability”': [1070], 'ℱ,': [1071], 'defined': [1072, 1396, 1568, 1889, 2584, 2987], 'ℱ': [1074, 1135, 1457, 1722, 2862, 2997, 3742], 'Δ/Γ,': [1076], 'where': [1077, 1486, 2187, 2501, 2587, 3215, 3998], 'measures': [1079, 1326, 1339], 'difference': [1081], 'free': [1084, 1108], 'native': [1088, 1220], 'state': [1089, 1226, 1599], 'respect': [1091], 'average': [1094, 1477, 1544, 1699, 2980, 3352], 'ensemble': [1097], 'states,': [1100], 'Γ': [1102], 'standard': [1105], 'deviation': [1106], 'ensemble.18,': [1113], '19': [1114, 4441], 'Based': [1115, 1942], 'simulations,': [1121, 2636], 'will': [1127, 2612, 2855, 3482], 'able': [1129], 'foldability': [1134, 1147, 1233, 1240, 1270, 1494, 1503, 1519, 1708, 1937, 2254, 3005, 3574, 3741, 3748], 'larger': [1137, 2158, 3537, 3744], 'critical': [1140, 3747], 'value': [1141, 1151, 1159, 1247, 1804, 2615], 'ℱcrit.20-23': [1142], 'All': [1143], 'above': [1148], 'ℱcrit': [1150, 1161, 1249, 1582, 1724, 1929, 1933, 1961, 1980, 1984, 1996, 2062, 2066, 2090, 2109, 2141, 2161, 2286, 2292, 2317, 2336, 2360, 2366, 2401, 2426, 2527, 2533, 2623, 2662, 2693, 2707, 2788, 2949, 3120], 'considered': [1153, 1323, 1726, 2408, 3571], 'fit.': [1157], 'might': [1162], 'aggregation': [1168], 'concentration': [1172], 'proteolytes,': [1174], 'presumably': [1177], 'altered': [1179], 'during': [1180, 2272, 2387, 2702, 2784, 2830, 3814, 3852], 'parameter': [1192], 'adjusted': [1196], 'simulate': [1198], 'differing': [1199], 'degrees': [1200], 'selective': [1202, 1309], 'pressure.': [1203], 'Given': [1204], 'sequence,': [1207, 2279, 2986, 3618, 3644], 'calculate': [1210], 'conformation,': [1221], 'assumed': [1222, 1246, 3731], 'lowest': [1228, 2959], 'energy,24': [1229], 'corresponding': [1232, 1597, 2347, 2514, 2542, 2659], 'ℱ.': [1234], 'then': [1237, 1808, 2606], 'compare': [1238], 'see': [1251, 3192, 3960], 'corresponds': [1254], 'protein.': [1258], 'sophisticated': [1261], 'proposed,25-29': [1268], 'criterion': [1271], 'computable': [1275], 'measure': [1276, 2562], 'ability,': [1279], 'described': [1284, 3818], 'computationally': [1286], 'tractable.': [1287], 'Previous': [1288], 'investigators': [1289, 1321, 2226], 'performed': [1291], 'minimizing': [1296], 'time': [1298, 2117, 3882], 'Monte': [1300], 'Carlo': [1301], 'simulations;': [1302], 'this,': [1303], 'assumes': [1305], 'an': [1306, 1441, 1476, 1698, 2714, 2803, 2849, 2909, 2963, 3067], 'priori': [1308], 'advantage': [1310, 3896], 'faster': [1312], 'rates': [1314, 2906, 3428], 'requires': [1316], 'extensive': [1317], 'time.30': [1319], 'Other': [1320, 3313], 'thermodynamic': [1325], 'indicative': [1329], 'ability31;': [1332], 'correlated': [1342], 'foldability.32': [1344], 'Four': [1345], 'explored': [1349, 1611], 'contrasted.': [1351], 'first': [1353], 'ignored': [1355], 'simply': [1362, 2814], 'computed': [1363, 2627], 'choosing': [1367], 'approximately': [1368, 1821], 'billion': [1370], 'evaluating': [1374], 'viability,': [1376], 'measuring': [1378], 'resulting': [1380, 1518, 1713, 3017, 3950], 'ground-state': [1383, 3753], 'provided': [1386, 4103], '𝒱k': [1391, 2305, 2321, 2543, 3272], 'proportion': [1399, 1910, 1950, 2990], 'second': [1410, 1514], 'third': [1412, 1554], 'methods': [1413], 'attempted': [1414, 1558], 'capture': [1416], 'dynamic': [1418], 'trajectory': [1426], 'diffusing': [1431], 'through': [1432, 1846], 'sequences.': [1438, 2044], 'Starting': [1439], 'initial': [1442, 1634, 1974, 2043, 2059, 2138, 2196, 3128], 'chosen': [1444, 1470, 1665, 1755], '(that': [1454], '>': [1458, 1723, 1981, 1997, 2998], 'ℱcrit),': [1459], 'randomly': [1463, 1761, 1912], 'mutated': [1464, 1671, 2993, 3118], 'mutations': [1469, 1488, 1556, 1679, 1689], 'Poisson': [1473, 1695, 1784], 'mutation': [1480, 1509, 1525, 1702, 1742, 3020, 3220], 'per': [1481, 1483, 1680, 1703, 1705], 'generation.': [1484, 1706, 2872], 'Generations': [1485], 'no': [1487, 4002], 'occurred': [1489], 'counted.': [1492], 'new': [1497, 1561, 2859], 'was': [1499, 1504, 1510, 1520, 1526, 1564, 1621, 1645, 1664, 1754, 2475, 3659, 3876, 4102], 'calculated;': [1500], 'greater': [1505, 4018], 'ℱcrit,': [1507, 1523, 1806, 2837, 2864, 2999, 3749], 'accepted.': [1511], 'model,': [1515, 1555], 'rejected': [1527], 'original': [1530], 'retained.': [1532], 'analogous': [1535], 'random-walk': [1537, 2352], 'which': [1540, 2154, 3619], 'particle': [1542], 'zero': [1545], 'velocity': [1546], 'when': [1547, 1581, 1616, 2252, 2404, 2425, 2787, 2838, 3867], 'boundary': [1549], 'encountered.': [1551], 'until': [1559], 'found.': [1565], 'myopic': [1571, 2018, 2103, 3189, 3213, 3248], 'walk.': [1572, 3256], 'Note': [1573], 'later': [1576], 'two': [1577, 2005, 2214, 3345], 'identical': [1580, 1640, 2357, 2524], '0': [1584, 1935, 1998, 2064, 2288, 2403, 2625, 2790], 'viable.': [1589, 2409], 'either': [1591], 'case,': [1592], 'ground': [1598, 3097], 'recorded': [1601, 1815], 'fifteen': [1603], 'million': [1604], 'generations.': [1605, 1824], 'fourth': [1607], 'changed': [1615], 'allowed': [1622, 1793], 'evolve,': [1624], 'reactor': [1628], 'flow': [1629], 'Eigen.33': [1632], 'An': [1633, 2472, 3653, 4042], 'N': [1637, 1651, 1752], '500': [1639], 'length': [1643], 'selected': [1646], 'containing': [1647], 'total': [1649, 1686], '×n': [1652], 'residues.': [1653, 3807], 'subsequent': [1656, 1817], 'generations,': [1657, 1800], 'residue': [1659], 'every': [1661, 1816], 'probability': [1667, 2805, 2851, 2875], '1/n': [1668], 'another': [1673, 1822, 3488], 'residue.': [1675], 'well': [1683, 2290], 'followed': [1693], 'distribution,': [1696, 1785], 'calculated,': [1716], 'N′': [1719, 1758], 'capable': [1729], 'reproducing.': [1731], 'mutational': [1733, 3092], 'death': [1734, 2877, 2966, 3079, 3353, 3361, 3381, 3427, 4024], 'whose': [1741], 'led': [1743], 'subcritical': [1746], 'fitness.': [1747], 'next': [1749, 2871], 'generation': [1750], 'surviving': [1759], 'replacement,': [1763], 'representing': [1764], 'stochastic': [1766], 'reproduction.': [1769], 'offspring': [1773], 'again': [1779, 3723], 'mean': [1787], 'N/N′.': [1788], "population's": [1790], 'equilibrate': [1795], '50,000': [1797], '200,000': [1799, 1823], 'depending': [1801], 'members': [1810], '100': [1818], 'generations': [1819], 'Such': [1825, 3091], 'modeled': [1830], 'investigators,': [1835], 'presence': [1839, 3457], 'clusters': [1841], 'diffuse': [1845], 'space.15': [1849], 'clustering': [1851], 'induced': [1853], 'reproduction': [1856], 'process,': [1857], 'high': [1861, 2439, 3024, 3426, 3442, 3480], 'extinction': [1864], 'others': [1873], 'population.': [1876, 3090, 3705], 'latter': [1879], 'three': [1880, 1926, 1972, 2042, 4059], 'methods,': [1881], 'compared': [1883], 'occupancy': [1887, 2268, 2353, 2520, 2593, 2929, 2944, 3486], '𝒪k,': [1888], 'evolutionarily': [1895, 4060], 'after': [1903], 'preequilibration,': [1904], '𝒱k,': [1908], 'sampled,': [1913, 2808], 'k.': [1921, 2596], 'four': [1924], 'models,': [1925], 'values': [1927, 1959, 2159, 2216, 2349, 2354, 2516, 2521, 2546, 2835], 'used,': [1931, 1977], '(no': [1936], 'requirement),': [1938], '3.5,': [1939, 2428, 2951], '4.5.': [1941, 1982], 'sequences,': [1948], 'remain': [1955, 3735], '100,': [1963], '14.3,': [1964], '0.15%,': [1966], 'respectively.': [1967], 'runs,': [1971], '0,': [1986, 2092], 'single-sequence': [1987, 2085, 2307, 2392, 2631, 2681], 'denoted': [1991, 2027], '𝒪,': [1993, 2265], 'whereas': [1994], 'differentiate': [2000], 'types': [2007], '𝒪': [2011, 2016, 2309, 2314, 2326, 2330, 2333, 2545, 3266], '(for': [2012, 2017], 'walks)': [2014], 'walks).': [2019], 'occupancies': [2021, 2047, 2074, 2132, 2308, 2313, 2325, 2329, 2382, 2393, 2416, 2434, 2461, 2572, 2682, 2701, 2728, 2813, 2888, 2961, 2971, 3195, 3245, 3332, 3431, 3443, 3715], '𝒪.': [2029], 'RESULTS': [2030], 'Sensitivity': [2031], 'Initial': [2033], 'Each': [2035], 'runs': [2038, 2078, 2660], 'repeated': [2040], 'largely': [2053, 2182, 3825], 'independent': [2054], 'choice': [2057], '3.5': [2068, 2368, 2535, 2664, 3122], '(average': [2069], 'correlation': [2070, 3555], 'coefficients': [2071], '1.00': [2080], '0.98': [2082], 'respectively,': [2093, 2645, 2675], '1.00,': [2095, 2096], '0.97': [2098], 'walk,': [2102, 2104], '3.5),': [2111], 'indicating': [2112, 2144], 'had': [2115], 'sufficient': [2116], 'explore': [2120], 'reach': [2125], 'steady': [2126], 'state.': [2127], 'contrast,': [2129, 2411, 3628], 'dependent': [2135], '4.5,': [2143], 'insufficient': [2145], 'sampling.': [2146], 'finding': [2148], 'agrees': [2149], 'earlier': [2151, 3568], 'work': [2152, 3569], 'demonstrated': [2156, 2245, 3580, 4047], 'induce': [2162], 'glassy': [2163], 'behavior,': [2164], 'become': [2169, 2181, 3085, 3518], 'slow,': [2170], 'nonexponential,': [2171], 'nonself-averaging.34,': [2173], '35': [2174, 4745], 'Under': [2175], 'conditions,': [2177], '“neutral': [2185], 'nets”': [2186], 'changes': [2192, 2889, 3296, 3813, 3831, 3851], 'retaining': [2194], 'reasons,': [2200], 'concentrate': [2202], 'rest': [2205], 'paper': [2208, 3821], 'obtained': [2211], 'smaller': [2215, 4023], 'ℱcrit.': [2218], 'Distribution': [2219, 2301, 3131], 'Designabilities': [2221], 'Occupancies': [2223, 2718, 2894, 3320], 'As': [2224, 2238, 2441, 2481, 3237, 3500, 3679], 'previous': [2225], 'noted,': [2228], 'observe': [2230, 4013], 'broad': [2232], '𝒱k.': [2237], 'Figure': [2241, 2295, 2339, 2448, 2506, 2921, 2976, 3036, 3106, 3240, 3321], 'previously,': [2246], 'becomes': [2249], 'broader': [2251, 2419, 2687, 3276], 'requirement': [2255, 2780], 'imposed.11,': [2257], '36': [2258, 4762], 'Figures': [2259, 2374], '2': [2262, 4131], 'show': [2263, 2924, 3483], 'walk': [2275, 2324, 3190, 3249], 'closely': [2280, 3250], 'follows': [2281], '3.5.': [2294, 2338, 2709], '1Open': [2296], 'figure': [2298, 2342, 2509, 3109], 'viewerPowerPoint': [2299, 2343, 2510, 3110], '(a)': [2300, 2363, 2530, 3111], '(——),': [2306, 2322], '(----),': [2310, 2327], '(–-–)': [2315, 2334], '0.0.': [2319], '(b)': [2320, 2539, 3130], 'myopic-walk': [2328], '(–––),': [2331], '2Open': [2340], 'Scatter': [2344, 2511], 'plots': [2345, 2512], 'displaying': [2346, 2513], '(𝒱k)': [2350, 2517], '[𝒪]': [2355], 'structures,': [2358, 2525, 2605, 2884, 3843], '0.0': [2362, 2529], '(b).': [2369, 2536], 'displayed': [2372], '3': [2377, 4144], 'demonstrate': [2378], 'match': [2390], 'case': [2399, 4052], 'near-zero': [2433], 'some': [2436], 'extremely': [2438], 'clear': [2443], 'insert': [2446], '3b,': [2449], 'there': [2450, 3216, 3384], 'more-than-linear': [2453], 'quantities,': [2457], 'roughly': [2462], 'proportional': [2463], 'raised': [2467], '1.45': [2470], 'power.': [2471], 'exponential': [2473], 'fit': [2474, 3515, 3526], 'clearly': [2476, 3988], 'inadequate': [2477], '(data': [2478], 'shown).': [2480], 'result,': [2483, 3681], 'lesser-designable': [2494], 'frequent': [2497], 'cases': [2500], 'neglected.': [2505], '3Open': [2507], 'population-simulation': [2519], '(𝒪)': [2522], 'Inset': [2537], 'shows': [2540, 2978, 3324], 'log–log': [2549], 'plot.': [2550], 'Also': [2551], 'best-fit': [2555], 'line': [2556], 'slope': [2558], '1.45.': [2559], 'useful': [2561], 'evenness': [2565], 'effective': [2580, 2619, 2654, 3262], 'size': [2582, 3264], 'Ωeff,': [2583], '(2)': [2586], 'Pk': [2588], 'If': [2597], 'quantities': [2599], 'distributed': [2601], 'evenly': [2602], 'Ω': [2604], 'Ωeff': [2607], 'Ω.': [2609], 'Uneven': [2610], 'distributions': [2611], 'reduce': [2613], 'Ωeff.': [2617], 'sizes': [2621, 2656], 'using': [2628], 'trajectories,': [2633], '985': [2638, 2640], '(𝒱k),': [2639, 2667], '(𝒪),': [2641, 2644, 2674], '984': [2643], 'within': [2646, 3399], 'scatter': [2649, 3341, 3538], 'runs.': [2652], '863': [2666], '864': [2668], '[𝒪],': [2669, 2671], '852': [2670], '683': [2673], 'highlighting': [2676], 'higher': [2692, 2965, 3062, 3485, 3710, 3714], 'values,': [2694], 'extreme': [2698], 'DISCUSSION': [2710], 'Population': [2711, 3319, 3923], 'Dynamics': [2712], 'Have': [2713], 'Effect': [2715], 'Observed': [2717, 3917], 'expect': [2721, 3958, 4011], "structures'": [2727], 'mirror': [2730], 'sample': [2742], 'unbiased': [2752], 'way.': [2753], 'Unsurprisingly,': [2754], 'trajectories': [2757], 'undergoing': [2761], 'fulfill': [2764, 3792], 'requirement,': [2766], 'providing': [2767], 'sufficiently': [2771], 'adequate': [2774], 'sampling': [2775, 3768], 'achieved.': [2778], 'similarly': [2782, 3491], 'fulfilled': [2783], 'cases,': [2799], 'being': [2807, 3877], 'so': [2810, 3467], 'reflect': [2815], 'degeneracies': [2818], 'mapping': [2821], 'situation': [2827, 3784], 'nonzero': [2834], 'large': [2840, 3338], 'nonviable.': [2846], 'appreciable': [2850], 'mutate': [2856], '<': [2863], 'die,': [2865], 'contribute': [2868], 'When': [2873], 'uniform': [2880], 'significantly.': [2890], 'Survival': [2891], 'Rates': [2892], 'Cause': [2893], 'Vary': [2896], 'More': [2897, 3913], 'Strongly': [2898], 'Than': [2899], 'Designability': [2900], 'Even': [2901], 'modest': [2902, 3830], 'survival': [2905, 2946, 2981, 3113], 'observable': [2910], '(see,': [2915], 'example,': [2917], 'Ref.': [2918], '37).': [2919], '3b': [2922, 3322], 'greater-than-linear,': [2934], 'power': [2935], 'law': [2936], 'dependence.': [2937], 'strong': [2941, 3621], 'rate.': [2947], 'At': [2948], '10%': [2953, 3143, 3154], '18%': [2964], 'top': [2974, 3142], '10%.': [2975], '4a': [2977], 'mutating': [2985, 3065], 'prior': [3009], 'mutation.': [3011], 'note': [3013, 3259], 'foldabilities': [3025, 3133], 'lower': [3034, 3051, 3268], 'foldabilities.': [3035], '4b': [3037], 'demonstrates': [3038], 'contain': [3043], 'foldable': [3046], 'Therefore,': [3053], 'average,': [3055], 'nonviable': [3068], 'Conversely,': [3070, 3706], 'robust': [3077], 'via': [3080], 'lethal': [3081], 'mutation,': [3082], 'robustness': [3093], 'due': [3094], 'well-defined': [3096], 'states': [3098], 'noted': [3102], 'RNA': [3104, 3507], 'structures.38': [3105], '4Open': [3107], 'Average': [3112], 'foldability.': [3129], '(——)': [3147], 'bottom': [3153], '(–-–).': [3158], 'area': [3160], 'under': [3161], 'curve': [3163], 'These': [3171], 'Results': [3172], 'Cannot': [3173], 'Fully': [3175], 'Explained': [3176], 'Basis': [3179], 'Connectivity': [3181], 'Sequence': [3184], 'Space': [3185], 'included': [3187], 'connectivity': [3206, 3228], 'space.': [3210, 3372], 'Single': [3211], 'walks,': [3214], 'successful': [3219], 'generation,': [3223], 'sensitive': [3225, 3376], 'way': [3231], 'not.': [3236], '1b,': [3241], 'matches': [3251], 'Although': [3257], '(indicating': [3273], 'slightly': [3275], 'occupancies),': [3279], 'change': [3281], 'small': [3283, 3378, 3387, 3828], 'including': [3289], 'dynamics.': [3291], 'indicates': [3293], 'inclusion': [3300], 'cannot': [3304], 'connectivity.': [3312], 'Factors': [3314], 'Are': [3315, 3912], 'Important': [3316], 'Determining': [3318], 'may': [3330, 3363, 3855, 3884, 3893], 'differ': [3334], 'relatively': [3337], 'factor.': [3339], 'reasons.': [3346], 'First,': [3347], 'imperfectly': [3356], 'correlated,': [3357], 'suggesting': [3358], 'depend': [3364], 'Occupancy': [3373], 'very': [3375], 'rates.': [3382], 'Second,': [3383], 'yet': [3388], 'significant': [3389], 'flux': [3391, 3416, 3453, 3548, 3758], 'Just': [3395], 'important,': [3403], 'viability': [3405], 'nearby': [3407, 3463], 'significant.': [3414], 'actually': [3417], 'reduces': [3418], 'occupancies,': [3422], 'low': [3430, 3472, 3492, 3631, 3690, 3696], 'tend': [3432, 3716, 3822, 3835], 'net': [3436, 3446], 'influx,': [3438], 'outflow.': [3448], 'magnitude': [3450], 'depends': [3454], 'alternative': [3459], 'space,': [3466], 'surrounded': [3474, 3523], 'neighboring': [3477], 'without': [3494], 'neighbors.': [3499], 'populations,': [3508], 'necessarily': [3512], 'populated.': [3521], 'Sequences': [3522], 'especially': [3525], 'neighbors': [3527, 3687, 3694], 'larger-than-expected': [3530], 'populations.15': [3531], 'Again,': [3532], 'occupancy.': [3545], 'reduced': [3551], 'because': [3552, 3603, 4016], 'its': [3561], 'maximum': [3573], 'optimizable,': [3583], 'thus': [3585, 3713], 'designable,': [3587], 'likely': [3592, 3968], 'structures.34': [3600], 'apart': [3615], 'impose': [3620], 'constraints': [3622, 3794], 'near': [3639], 'inverted': [3654], 'form': [3655], 'argument': [3658], 'Tang': [3662], 'co-workers,': [3664], 'having': [3668], 'itself': [3675], 'increase': [3676], 'designability.39': [3678], 'generally': [3688], 'reducing': [3698], 'opportunity': [3700, 3725], 'substantial': [3702], 'redistribution': [3703], 'fewer': [3719], 'neighbors,': [3721], 'flux.': [3728], 'remains': [3743], 'changes.': [3755], 'essential': [3760], 'simulation': [3763, 3817, 3854], 'provide': [3767], 'unclear': [3777], 'assumption': [3781], 'reflects': [3782], 'biological': [3786], 'functional': [3793, 3806], 'often': [3796], 'rely': [3797], 'maintaining': [3799], 'geometrical': [3802], 'arrangement': [3803], 'On': [3808], 'hand,': [3811], 'native-state': [3812], 'conservative,': [3826], 'conserving': [3844], 'local': [3846], 'configurations.': [3847], 'Finally,': [3848], 'allowing': [3849], 'appropriate': [3858], 'modeling': [3860], 'beginning': [3862], 'stages': [3863], 'determined,': [3878], '“finely': [3889], 'tuned”': [3890], 'catalysis': [3892], 'taken': [3895], 'generic': [3899], 'acid': [3907], 'Highly': [3909], 'Designable': [3910], 'Structures': [3911], 'Likely': [3914], 'Direct': [3920], 'Result': [3921], 'Evolution': [3924], 'overrepresentation': [3926], 'certain': [3928], 'striking': [3936], 'indicate': [3944], 'interpret': [3947], 'convergent': [3953, 3961], 'divergent': [3955, 4014], 'evolve': [3973], 'lesser': [3984], 'designability.': [3985], 'evident': [3989], 'categorization': [3991], 'systems': [3992], 'SCOP': [3996], 'database,': [3997], 'seemingly': [4001], 'structures.4': [4007], 'available': [4019], 'give': [4031], 'flexibility': [4033], 'novel': [4040], 'functions.': [4041], 'example': [4043], 'yeast': [4049], 'Cdc25': [4055], 'appearing': [4057], 'quite': [4064], 'functions;': [4066], 'rhodanese,': [4067], 'Map': [4069], 'Kinase': [4070], 'phosphatase': [4071], 'noncatalytic': [4072], 'domain,': [4073], 'arsenate': [4076], 'resistance': [4077], 'ACR2.40': [4079], 'Acknowledgements': [4080], 'like': [4083], 'thank': [4085], 'Nicolas': [4086], 'Buchler': [4087], 'Sridhar': [4089], 'helpful': 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4448, 4567, 4588, 4645], 'G.': [4404, 4427, 4450, 4569, 4590, 4647], '84,': [4411], '7524–': [4412], '7528.': [4413], '18': [4418], 'Luthey-Schulten,': [4422, 4445, 4565], 'Z.': [4423, 4446], '89,': [4434, 4457], '4918–': [4435], '4922.': [4436], '9029–': [4458], '9033.': [4459], '20': [4464], 'Šali,': [4465, 4485], 'I.;': [4469, 4489, 4506, 4662], 'Karplus,': [4470, 4490], '235,': [4477], '1614–': [4478], '1636.': [4479], '369,': [4496], '248–': [4497], '251.': [4498], '22': [4503], 'Abkevich,': [4504, 4660], 'V.': [4505, 4604, 4661, 4851], 'Phys': [4515, 4533, 4572, 4593, 4650, 4710], '101,': [4517], '6052–': [4518], '6062.': [4519], '23': [4524], 'Betancourt,': [4525], 'Onuchic,': [4528, 4562, 4642], '103,': [4535], '773–': [4536], '787.': [4537], '24': [4542], '95,': [4554, 4693, 4829], '5545–': [4555], '5549.': [4556], 'N.;': [4564, 4644], 'Z.;': [4566], 'Annu': [4570], 'Rev': [4571], '48,': [4575], '545–': [4576], '600.': [4577], '26': [4582], 'Plotkin,': [4583], 'Wang,': [4586], 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